Patent application title: ANTI-SERUM ALBUMIN BINDING VARIANTS
Inventors:
Elena De Angelis (Brentford, GB)
Carolyn Enever (Brentford, GB)
Haiqun Liu (Brentford, GB)
Oliver Schon (Brentford, GB)
Malgorzata Pupecka-Swider (Stevenage, GB)
Assignees:
GLAXO GROUP LIMITED
IPC8 Class: AC07K1618FI
USPC Class:
Class name:
Publication date: 2015-10-08
Patent application number: 20150284454
Abstract:
The invention relates to improved variants of the anti-serum albumin
immunoglobulin single variable domain DOM7h-11, as well as ligands and
drug conjugates comprising such variants, compositions, nucleic acids,
vectors and hosts.Claims:
1. An anti-serum albumin (SA) immunoglobulin single variable domain
variant of DOM7h-11 (SEQ ID NO: 438), said variant having a Tm of at
least 54.degree. C.
2. An anti-SA immunoglobulin as claimed in claim 1, wherein said variant comprises at least one mutation at position 22, 42 or 91 (numbering according to Kabat) compared to DOM7h-11, and, wherein said variant is a variant of DOM7h-11-15 (SEQ ID NO: 2) and comprises at least one mutation at position 22, 42, or 91 (numbering according to Kabat) compared to DOM7h-11-15.
3. The variant of any of claim 1, wherein the variant comprises at least one mutation selected from the following: Position 22=Ser, Phe, Thr, Ala or Cys; Position 42=Glu or Asp; Position 91=Thr or Ser.
4. An anti-SA immunoglobulin single variable domain variant as claimed in claim 3 wherein position 22 is Ser or Phe; or wherein position 42 is Glu and position 91 is Thr; or wherein position 91 is Thr; or wherein position 22 is Phe.
5. The variant of claim 1, wherein the variant comprises an amino acid sequence that is identical to the amino acid sequence of a single variable domain selected from DOM7h-11-56 (SEQ ID NO: 412), DOM7h-11-68 (SEQ ID NO: 416), DOM7h-11-79 (SEQ ID NO:418), DOM7h-11-80 (SEQ ID NO: 419), DOM 7h-11-90 (SEQ ID NO: 420), DOM 7h-11-86 (SEQ ID NO: 421), DOM 7h-11-87 (SEQ ID NO: 422), and DOM 7h-11-88 (SEQ ID NO: 423) or has up to 4 changes compared to the selected amino acid sequence.
6. An anti-SA immunoglobulin single variable domain variant as claimed in claim 1 wherein the variant comprises at least one mutation in the FW3 region (positions 57 to 88, numbering according to Kabat) or in the CDR3 region (positions 89 to 97, numbering according to Kabat) compared to DOM7h-11, preferably wherein said variant is a variant of DOM7h-11-15 (SEQ ID NO: 2) and comprises at least one mutation in the FW3 region (positions 57 to 88, numbering according to Kabat) or in the CDR3 region (positions 89 to 97, numbering according to Kabat) compared to DOM7h-11-15.
7. An anti-SA immunoglobulin single variable domain variant as claimed in claim 6 wherein said variant comprises at least one mutation at any of positions 77, 83, 93 or 95 (numbering according to Kabat), and, preferably, wherein the variant comprises at least one mutation selected from the following: Position 77=Asn, Gln Position 83=Val, Ile, Met, Leu, Phe, Ala or Norleucine. Position 93=Val, Ile, Met, Leu, Phe, Ala or Norleucine. Position 95=His, Asn, Gln, Lys or Arg.
8. An anti-SA immunoglobulin single variable domain as claimed in claim 1 further comprising a mutation at position 106 or 108 (numbering according to Kabat); preferably wherein position 106 is Asn or Gln; or wherein position 108 is Trp, Tyr or Phe.
9. An anti-SA immunoglobulin single variable domain variant as claimed in claim 1 wherein position 77 is Asn; or wherein position 83 is Val; or wherein position 95 is His; or wherein position 93 is Val.
10. An anti-serum albumin (SA) immunoglobulin single variable domain variant of DOM7h-11 (SEQ ID NO: 438), said variant having a Tm of at least 54.degree. C., wherein the variant comprises an amino acid sequence that is identical to the amino acid sequence of a single variable domain selected from DOM7h-11-57 (SEQ ID NO: 413), DOM7h-11-65 (SEQ ID NO: 414), DOM7h-11-67 (SEQ ID NO:415) and DOM7h-11-69 (SEQ ID NO: 417) or has up to 4 changes compared to the selected amino acid sequence, provided that the amino acid sequence of the variant has at least one mutation in the FW3 or CDR3 region as defined in of claim 1.
11. A variant as claimed in claim 6 said variant having a Tm of at least 57.degree. C.
12. A variant as claimed in claim 1, wherein said variant has an increased Tm value compared to DOM7h-11, or an increased Tm value compared to DOM7h-11-15.
13. The variant of claim 1, wherein a) the variant comprises a binding site that specifically binds human SA with a dissociation constant (KD) of from about 0.1 to about 10000 nM, optionally from about 1 to about 6000 nM, as determined by surface plasmon resonance; or b) the variant comprises a binding site that specifically binds human SA with an off-rate constant (Kd) of from about 1.5.times.10.sup.-4 to about 0.1 sec-1, optionally from about 3.times.10.sup.-4 to about 0.1 sec-1 as determined by surface plasmon resonance; or c) the variant comprises a binding site that specifically binds human SA with an on-rate constant (Ka) of from about 2.times.10.sup.6 to about 1.times.10.sup.4M-1 sec-1, optionally from about 1.times.10.sup.6 to about 2.times.10.sup.4 M-1 sec-1 as determined by surface plasmon resonance; or d) the variant comprises a binding site that specifically binds Cynomolgus monkey SA with a dissociation constant (KD) of from about 0.1 to about 10000 nM, optionally from about 1 to about 6000 nM, as determined by surface plasmon resonance; or e) the variant comprises a binding site that specifically binds Cynomolgus monkey SA with an off-rate constant (Kd) of from about 1.5.times.10.sup.-4 to about 0.1 sec-1, optionally from about 3.times.10.sup.-4 to about 0.1 sec-1 as determined by surface plasmon resonance; or f) the variant comprises a binding site that specifically binds Cynomolgus monkey SA with an on-rate constant (Ka) of from about 2.times.10.sup.6 to about 1.times.10.sup.4M-1 sec-1, optionally from about 1.times.10.sup.6 to about 5.times.10.sup.3M-1 sec-1 as determined by surface plasmon resonance.
14. A multispecific ligand comprising an anti-SA variant of claim 1 and a binding moiety that specifically binds a target antigen other than SA.
15. An anti-SA variant single variable domain of claim 1, wherein the variable domain is conjugated to a drug (optionally an NCE drug), optionally wherein the selected variant is DOM7h-11-56 (SEQ ID NO: 412), DOM7h-11-57 (SEQ ID NO: 413), DOM7h-11-65 (SEQ ID NO: 414), DOM7h-11-67 (SEQ ID NO:415), DOM7h-11-68 (SEQ ID NO:416), DOM7h-11-69 (SEQ ID NO: 417), DOM7h-11-79 (SEQ ID NO:418), DOM7h-11-80 (SEQ ID NO:419), DOM7h-11-90 (SEQ ID NO:420), DOM7h-11-86 (SEQ ID NO:421), DOM7h-11-87 (SEQ ID NO:422) or DOM7h-11-88 (SEQ ID NO:423).
16. A fusion protein comprising a polypeptide or peptide drug fused to a variant according to claim 1, optionally wherein the selected variant is DOM7h-11-56 (SEQ ID NO: 412), DOM7h-11-57 (SEQ ID NO: 413), DOM7h-11-65 (SEQ ID NO: 414), DOM7h-11-67 (SEQ ID NO:415), DOM7h-11-68 (SEQ ID NO:416), DOM7h-11-69 (SEQ ID NO: 417), DOM7h-11-79 (SEQ ID NO:418), DOM7h-11-80 (SEQ ID NO:419), DOM7h-11-90 (SEQ ID NO:420), DOM7h-11-86 (SEQ ID NO:421), DOM7h-11-87 (SEQ ID NO:422) or DOM7h-11-88 (SEQ ID NO:423), preferably wherein the fusion protein comprises a linker (e.g., a linker comprising the amino acid sequence TVA, optionally TVAAPS) between the variant and the drug.
17. A composition comprising a variant, fusion protein or ligand of claim 1 and a pharmaceutically acceptable diluent, carrier, excipient or vehicle.
18. A method of treating or preventing a disease or disorder in a patient, comprising administering at least one dose of a variant, multispecific ligand or fusion protein according to claim 1 to said patient.
Description:
[0001] The invention relates to improved variants of the anti-serum
albumin immunoglobulin single variable domain DOM7h-11, as well as
ligands and drug conjugates comprising such variants, compositions,
nucleic acids, vectors and hosts.
BACKGROUND OF THE INVENTION
[0002] WO04003019 and WO2008/096158 disclose anti-serum albumin (SA) binding moieties, such as anti-SA immunoglobulin single variable domains (dAbs), which have therapeutically-useful half-lives. These documents disclose monomer anti-SA dAbs as well as multi-specific ligands comprising such dAbs, e.g., ligands comprising an anti-SA dAb and a dAb that specifically binds a target antigen, such as TNFR1. Binding moieties are disclosed that specifically bind serum albumins from more than one species, e.g. human/mouse cross-reactive anti-SA dAbs.
[0003] WO05118642 and WO2006/059106 disclose the concept of conjugating or associating an anti-SA binding moiety, such as an anti-SA immunoglobulin single variable domain, to a drug, in order to increase the half-life of the drug. Protein, peptide and new chemical entity (NCE) drugs are disclosed and exemplified. WO2006/059106 discloses the use of this concept to increase the half-life of insulintropic agents, e.g., incretin hormones such as glucagon-like peptide (GLP)-1. Reference is also made to Holt et al, "Anti-Serum albumin domain antibodies for extending the half-lives of short lived drugs", Protein Engineering, Design & Selection, vol 21, no 5, pp 283-288, 2008. WO2008/096158 discloses DOM7h-11, which is a good anti-SA dAb. It would be desirable to provide improved dAbs that are variants of DOM7h-11 and that specifically bind serum albumin, preferably albumins from human and non-human species, which would provide utility in animal models of disease as well as for human therapy and/or diagnosis. It would also be desirable to provide for the choice between relatively modest- and high-affinity anti-SA binding moieties (dAbs). Such moieties could be linked to drugs, the anti-SA binding moiety being chosen according to the contemplated end-application. This would allow the drug to be better tailored to treating and/or preventing chronic or acute indications, depending upon the choice of anti-SA binding moiety. It would also be desirable to provide anti-SA dAbs, that are monomeric or substantially so in solution. This would especially be advantageous when the anti-SA dAb is linked to a binding moiety, e.g., a dAb, that specifically binds a cell-surface receptor, such as TNFR1, with the aim of antagonizing the receptor. The monomeric state of the anti-SA dAb is useful in reducing the chance of receptor cross-linking, since multimers are less likely to form which could bind and cross-link receptors (e.g., TNFR1) on the cell surface, thus increasing the likelihood of receptor agonism and detrimental receptor signaling.
[0004] A number of improved dAbs are disclosed in PCT/EP2010/052008 and PCT/EP2010/052007 the disclosures of which are incorporated by reference.
[0005] It would also be desirable to provide improved dAbs that have an improved stability. This would be advantageous in allowing a dAb to have a suitable stability profile or shelf-life. In particular, it would be desirable to provide dAbs having an improved ability to resist unfolding upon exposure to elevated temperatures i.e. improved thermostability. It would also be desirable to provide dAbs that have improved stability when formatted into constructs such as multi-specific ligands or when conjugated to proteins, peptides or NCEs.
SUMMARY OF THE INVENTION
[0006] Aspects of the present invention solve these problems.
[0007] To this end, the present inventors surprisingly found that mutations can be made to immunoglobulin single variable domain molecules of the DOM7h-11 lineage to give the molecules improved stability as measured by an improved thermostability relative to the parent DOM7h-11 molecules.
[0008] In one aspect, there is provided an anti-serum albumin (SA) immunoglobulin single variable domain variant of DOM7h-11 (DOM7h-11 as shown in FIG. 1), said variant having a Tm of at least 54° C. In another aspect, there is provided an anti-serum albumin (SA) immunoglobulin single variable domain variant of DOM7h-11 (DOM7h-11 as shown in FIG. 1), said variant having a Tm of greater than 54° C. The transition midpoint (Tm) is the temperature where 50% of the protein is in its native conformation and the other 50% is denatured. Suitably said Tm is measured by Differential Scanning calorimetry.
[0009] In one embodiment, said variant comprises at least one mutation in any of positions 22, 42 or 91 (numbering according to Kabat) compared to DOM7h-11.
[0010] Suitably, an anti-SA immunoglobulin single variable domain variant is a variant of DOM7h-11-15 (DOM7h-11-15 as shown in FIG. 1 (SEQ ID NO: 7) and comprises at least one mutation in any of positions 22, 42 or 91 (numbering according to Kabat) compared to DOM7h-11-15. In one embodiment, a variant comprises at least one mutation selected from the following:
Position 22=Ser, Phe, Thr, Ala or Cys;
Position 42=Glu or Asp;
Position 91=Thr or Ser;
[0011] In other embodiments, there is provided an anti-SA immunoglobulin single variable domain variant wherein position 22 is Ser or Phe; an anti-SA immunoglobulin single variable domain variant wherein position 42 is Glu and position 91 is Thr; an anti-SA immunoglobulin single variable domain variant wherein position 91 is Thr; an anti-SA immunoglobulin single variable domain variant wherein position 22 is Phe. In one embodiment, position 108 is Trp.
[0012] Further embodiments provide a variant comprising an amino acid sequence that is identical to the amino acid sequence of a single variable domain selected from DOM7h-11-56 (SEQ ID NO: 412), DOM7h-11-68 (SEQ ID NO: 416), DOM7h-11-79 (SEQ ID NO:418) and DOM7h-11-80 (SEQ ID NO: 419) (or a variant having an amino acid that is at least 95, 96, 97, 98 or 99% identical to the amino acid sequence of the selected amino acid sequence) or has up to 4 changes compared to the selected amino acid sequence.
[0013] In particular, it has been found that mutations targeted to the FW3 (positions 57 to 88, numbering according to Kabat) and CDR3 regions (positions 89 to 97, numbering according to Kabat) of DOM7h-11 confer improved stability. Accordingly, in another embodiment, there is provided an anti-SA immunoglobulin single variable domain variant in accordance with an aspect of the invention wherein the variant comprises at least one mutation in the FW3 region (positions 57 to 88, numbering according to Kabat) or in the CDR3 region (positions 89 to 97, numbering according to Kabat) compared to DOM7h-11.
[0014] Further embodiments provide an anti-SA immunoglobulin single variable domain variant wherein said variant is a variant of DOM7h-11-15 (DOM7h-11-15 as shown in FIG. 1) and comprises at least one mutation in the FW3 region (positions 57 to 88, numbering according to Kabat) or in the CDR3 region (positions 89 to 97, numbering according to Kabat) compared to DOM7h-11-15. Suitably, said variant comprises at least one mutation at any of positions 77, 83, 93 or 95 (numbering according to Kabat).
[0015] In one embodiment, the variant comprises at least one mutation selected from the following:
Position 77=Asn, Gln
Position 83=Val, Ile, Met, Leu, Phe, Ala or Norleucine.
Position 93=Val, Ile, Met, Leu, Phe, Ala or Norleucine.
Position 95=His, Asn, Gln, Lys or Arg.
[0016] In another embodiment, an anti-SA immunoglobulin single variable domain in accordance with the invention further comprises a mutation at position 106 or 108 (numbering according to Kabat). Suitably, position 106 is Asn or Gln. Suitably position 108 is Tip, Tyr or Phe.
[0017] In further embodiments, there is provided an anti-SA immunoglobulin single variable domain variant wherein position 77 is Asn; an anti-SA single variable domain wherein position 83 is Val; an anti-SA single variable domain wherein position 95 is His; an anti-SA single variable domain wherein position 95 is His; an anti-SA single variable domain wherein position 93 is Val.
[0018] In yet further embodiments, there is provided a variant comprising an amino acid sequence that is identical to the amino acid sequence of a single variable domain selected from DOM7h-11-57 (SEQ ID NO: 413), DOM7h-11-65 (SEQ ID NO: 414) or DOM7h-11-67 (SEQ ID NO:415) (or a variant having an amino acid that is at least 95, 96, 97, 98 or 99% identical to the amino acid sequence of the selected amino acid sequence) or has up to 4 changes compared to the selected amino acid sequence, provided that the amino acid sequence of the variant has at least one mutation in the FW3 or CDR3 region.
[0019] In further embodiments, there is provided a variant comprising an amino acid sequence that is identical to the amino acid sequence of a single variable domain selected from DOM7h-11-69 (SEQ ID NO: 417), DOM 7h-11-90 (SEQ ID NO: 420), DOM 7h-11-86 (SEQ ID NO: 421), DOM 7h-11-87 (SEQ ID NO: 422), or DOM 7h-11-88 (SEQ ID NO: 423) (or a variant having an amino acid that is at least 95, 96, 97, 98 or 99% identical to the amino acid sequence of the selected amino acid sequence).
[0020] Suitably a variant has a Tm of at least 57° C. In another embodiment, a variant has a Tm of greater than 57° C.
[0021] In one embodiment, a variant in accordance with any embodiment of the invention has an increased Tm value compared to DOM7h-11. In another embodiment, said variant has an increased Tm value compared to DOM7h-11-15. In another embodiment, there is provided a variant comprising any combination of any of the mutations listed above. Suitably, Tm is measured by DSC in accordance with the methods described herein.
[0022] Suitably, a variant in accordance with the invention comprises a binding site that specifically binds human SA with a dissociation constant (KD) of from about 0.1 to about 10000 nM, optionally from about 1 to about 6000 nM, as determined by surface plasmon resonance. The variant of any preceding claim, wherein the variant comprises a binding site that specifically binds human SA with an off-rate constant (Kd) of from about 1.5×10-4 to about 0.1 sec-1, optionally from about 3×10-4 to about 0.1 sec-1 as determined by surface plasmon resonance. The variant of any preceding claim, wherein the variant comprises a binding site that specifically binds human SA with an on-rate constant (Ka) of from about 2×106 to about 1×104M-1 sec-1, optionally from about 1×106 to about 2×104M-1 sec-1 as determined by surface plasmon resonance.
[0023] Advantageously, the variant in accordance with the invention is cross-reactive with serum albumin from a number of different species such as, for example, monkey e.g. Cynomolgus monkey, suncus (shrew), marmoset, ferret, rat, mouse, pig and dog SA.
[0024] Accordingly, in one embodiment, the variant in accordance with the invention comprises a binding site that specifically binds Cynomolgus monkey SA with a dissociation constant (KD) of from about 0.1 to about 10000 nM, optionally from about 1 to about 6000 nM, as determined by surface plasmon resonance. The variant of any preceding claim, wherein the variant comprises a binding site that specifically binds Cynomolgus monkey SA with an off-rate constant (Kd) of from about 1.5×10-4 to about 0.1 sec-1, optionally from about 3×10-4 to about 0.1 sec-1 as determined by surface plasmon resonance. The variant of any preceding claim, wherein the variant comprises a binding site that specifically binds Cynomolgus monkey SA with an on-rate constant (Ka) of from about 2×106 to about 1×104M-1 sec-1, optionally from about 1×106 to about 5×103M-1 sec-1 as determined by surface plasmon resonance. In another aspect, there is provided a multispecific ligand comprising an anti-SA variant in accordance with the invention and a binding moiety that specifically binds a target antigen other than SA. Suitable target antigens are exemplified herein. In one embodiment, the binding moiety that specifically binds a target antigen may be another single domain immunoglobulin molecule. In another embodiment, the binding moiety that specifically binds a target antigen may be a monoclonal antibody. Suitable formats and methods for making dual specific molecules, such as mAbdAb molecules are described, for example in WO2009/068649.
[0025] An aspect of the invention provides a fusion product, e.g., a fusion protein or fusion with a peptide or NCE (new chemical entity) drug, comprising a polypeptide, protein, peptide or NCE drug fused or conjugated (for an NCE) to any variant as described above. In another aspect, there is provided a fusion protein, polypeptide fusion or conjugate comprising a polypeptide or peptide drug fused to an anti-serum albumin dAb variant in accordance with the invention, optionally wherein the selected variant is DOM7h-11-56 (SEQ ID NO: 412), DOM7h-11-57 (SEQ ID NO: 413), DOM7h-11-65 (SEQ ID NO: 414), DOM7h-11-67 (SEQ ID NO:415), DOM7h-11-68 (SEQ ID NO:416), DOM7h-11-69 (SEQ ID NO: 417), DOM7h-11-79 (SEQ ID NO:418), DOM7h-11-80 (SEQ ID NO: 419), DOM 7h-11-90 (SEQ ID NO: 420), DOM 7h-11-86 (SEQ ID NO: 421), DOM 7h-11-87 (SEQ ID NO: 422), or DOM 7h-11-88 (SEQ ID NO: 423). Suitably, such a fusion protein comprises a linker (e.g., a linker comprising the amino acid sequence TVA, optionally TVAAPS (SEQ ID NO: 437) between the variant and the drug.
[0026] In one embodiment, there is provided a polypeptide fusion or conjugate comprising an anti-serum albumin dAb as disclosed herein and an incretin or insulinotropic agent, e.g., exendin-4, GLP-1(7-37), GLP-1(6-36) or any incretin or insulinotropic agent disclosed in WO06/059106, these agents being explicitly incorporated herein by reference as though written herein for inclusion in the present invention and claims below.
[0027] In another aspect, there is provided an anti-SA variant single variable domain in accordance with the invention, wherein the variable domain is conjugated to a drug (optionally an NCE drug), optionally wherein the selected variant is DOM7h-11-56 (SEQ ID NO: 412), DOM7h-11-57 (SEQ ID NO: 413), DOM7h-11-65 (SEQ ID NO: 414), DOM7h-11-67 (SEQ ID NO:415), DOM7h-11-68 (SEQ ID NO:416), DOM7h-11-69 (SEQ ID NO: 417), DOM7h-11-79 (SEQ ID NO:418), DOM7h-11-80 (SEQ ID NO: 419), DOM 7h-11-90 (SEQ ID NO: 420), DOM 7h-11-86 (SEQ ID NO: 421), DOM 7h-11-87 (SEQ ID NO: 422), or DOM 7h-11-88 (SEQ ID NO: 423).
[0028] In another aspect there is provided a composition comprising a variant, fusion protein or ligand of any preceding claim and a pharmaceutically acceptable diluent, carrier, excipient or vehicle.
[0029] In a further aspect, there is provided a nucleic acid comprising a nucleotide sequence encoding a variant according to the invention or a multispecific ligand or fusion protein in accordance with the invention. Suitably, there is provided a nucleic acid comprising the nucleotide sequence of a DOM7h-11 variant selected from the nucleotide sequence of DOM7h-11-56 (SEQ ID NO: 425), DOM7h-11-57 (SEQ ID NO: 426), DOM7h-11-65 (SEQ ID NO: 427), DOM7h-11-67 (SEQ ID NO:428), DOM7h-11-68 (SEQ ID NO:429), DOM7h-11-69 (SEQ ID NO: 430), DOM7h-11-79 (SEQ ID NO:431), DOM7h-11-80 (SEQ ID NO: 432), DOM 7h-11-90 (SEQ ID NO: 433), DOM 7h-11-86 (SEQ ID NO: 434), DOM 7h-11-87 (SEQ ID NO: 435), or DOM 7h-11-88 (SEQ ID NO: 436) or a nucleotide sequence that is at least 80% identical to said selected sequence.
[0030] Another aspect provides a vector comprising a nucleic acid in accordance with the invention. A further aspect provides an isolated host cell comprising a vector of the invention.
[0031] In a further aspect there is provided a method of treating or preventing a disease or disorder in a patient, comprising administering at least one dose of a variant in accordance with any aspect or embodiment of the invention to said patient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1A-1B: Amino-acid sequence alignment for DOM7h-11 variant dAbs. A "." at a particular position indicates the same amino as found in DOM7h-11 at that position. The CDRs are indicated by underlining and bold text (the first underlined sequence is CDR1, the second underlined sequence is CDR2 and the third underlined sequence is CDR3).
[0033] FIG. 2A-2D: Kinetic parameters of DOM7h-11 variants. KD units=nM; Kd units=sec-1; Ka units=M-1 sec-1. The notation A e-B means A×10-B and C e D means C×10D. The overall kinetic ranges in various species, as supported by the examples below, are indicated. Optional ranges are also provided for use in particular therapeutic settings (acute or chronic indications, conditions or diseases and "intermediate" for use in both chronic and acute settings). High affinity dAbs and products comprising these are useful for chronic settings. Medium affinity dAbs and products comprising these are useful for intermediate settings. Low affinity dAbs and products comprising these are useful for acute settings. The affinity in this respect is the affinity for serum albumin. Various example anti-serum dAbs and fusion proteins are listed, and these support the ranges disclosed. Many of the examples have favourable kinetics in human and one or more non-human animals (e.g., in human and Cynomolgus monkey and/or mouse). Choice of dAb or product comprising this can be tailored, according to the invention, depending on the setting (e.g., chronic or acute) to be treated therapeutically.
[0034] FIG. 3A-3B: Amino-acid (A) and nucleic acid (B) sequence alignment for DOM7h-11-15 variant dAbs. A "." at a particular position indicates the same amino as found in DOM7h-11-15 at that position.
DETAILED DESCRIPTION OF THE INVENTION
[0035] Within this specification the invention has been described, with reference to embodiments, in a way which enables a clear and concise specification to be written. It is intended and should be appreciated that embodiments may be variously combined or separated without parting from the invention.
[0036] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in cell culture, molecular genetics, nucleic acid chemistry, hybridization techniques and biochemistry). Standard techniques are used for molecular, genetic and biochemical methods (see generally, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. and Ausubel et al., Short Protocols in Molecular Biology (1999) 4th Ed, John Wiley & Sons, Inc. which are incorporated herein by reference) and chemical methods.
[0037] As used herein, the term "antagonist of Tumor Necrosis Factor Receptor 1 (TNFR1)" or "anti-TNFR1 antagonist" or the like refers to an agent (e.g., a molecule, a compound) which binds TNFR1 and can inhibit a (i.e., one or more) function of TNFR1. For example, an antagonist of TNFR1 can inhibit the binding of TNFα to TNFR1 and/or inhibit signal transduction mediated through TNFR1. Accordingly, TNFR1-mediated processes and cellular responses (e.g., TNFα-induced cell death in a standard L929 cytotoxicity assay) can be inhibited with an antagonist of TNFR1.
[0038] A "patient" is any animal, e.g., a mammal, e.g., a non-human primate (such as a baboon, rhesus monkey or Cynomolgus monkey), mouse, human, rabbit, rat, dog, cat or pig. In one embodiment, the patient is a human.
[0039] As used herein, "peptide" refers to about two to about 50 amino acids that are joined together via peptide bonds.
[0040] As used herein, "polypeptide" refers to at least about 50 amino acids that are joined together by peptide bonds. Polypeptides generally comprise tertiary structure and fold into functional domains.
[0041] As used herein an antibody refers to IgG, IgM, IgA, IgD or IgE or a fragment (such as a Fab, Fab', F(ab')2, Fv, disulphide linked Fv, scFv, closed conformation multispecific antibody, disulphide-linked scFv, diabody) whether derived from any species naturally producing an antibody, or created by recombinant DNA technology; whether isolated from serum, B-cells, hybridomas, transfectomas, yeast or bacteria.
[0042] As used herein, "antibody format" refers to any suitable polypeptide structure in which one or more antibody variable domains can be incorporated so as to confer binding specificity for antigen on the structure. A variety of suitable antibody formats are known in the art, such as, chimeric antibodies, humanized antibodies, human antibodies, single chain antibodies, bispecific antibodies, antibody heavy chains, antibody light chains, homodimers and heterodimers of antibody heavy chains and/or light chains, antigen-binding fragments of any of the foregoing (e.g., a Fv fragment (e.g., single chain Fv (scFv), a disulfide bonded Fv), a Fab fragment, a Fab' fragment, a F(ab')2 fragment), a single antibody variable domain (e.g., a dAb, VH, VHH, VL), and modified versions of any of the foregoing (e.g., modified by the covalent attachment of polyethylene glycol or other suitable polymer or a humanized VHH).
[0043] The phrase "immunoglobulin single variable domain" refers to an antibody variable domain (VH, VHH, VL) that specifically binds an antigen or epitope independently of different V regions or domains. An immunoglobulin single variable domain can be present in a format (e.g., homo- or hetero-multimer) with other variable regions or variable domains where the other regions or domains are not required for antigen binding by the single immunoglobulin variable domain (i.e., where the immunoglobulin single variable domain binds antigen independently of the additional variable domains). A "domain antibody" or "dAb" is the same as an "immunoglobulin single variable domain" as the term is used herein. A "single immunoglobulin variable domain" is the same as an "immunoglobulin single variable domain" as the term is used herein. A "single antibody variable domain" or an "antibody single variable domain" is the same as an "immunoglobulin single variable domain" as the term is used herein. An immunoglobulin single variable domain is in one embodiment a human antibody variable domain, but also includes single antibody variable domains from other species such as rodent (for example, as disclosed in WO 00/29004, the contents of which are incorporated herein by reference in their entirety), nurse shark and Camelid VHH dAbs. Camelid VHH are immunoglobulin single variable domain polypeptides that are derived from species including camel, llama, alpaca, dromedary, and guanaco, which produce heavy chain antibodies naturally devoid of light chains. The VHH may be humanized.
[0044] A "domain" is a folded protein structure which has tertiary structure independent of the rest of the protein. Generally, domains are responsible for discrete functional properties of proteins, and in many cases may be added, removed or transferred to other proteins without loss of function of the remainder of the protein and/or of the domain. A "single antibody variable domain" is a folded polypeptide domain comprising sequences characteristic of antibody variable domains. It therefore includes complete antibody variable domains and modified variable domains, for example, in which one or more loops have been replaced by sequences which are not characteristic of antibody variable domains, or antibody variable domains which have been truncated or comprise N- or C-terminal extensions, as well as folded fragments of variable domains which retain at least the binding activity and specificity of the full-length domain.
[0045] A "lineage" refers to a series of immunoglobulin single variable domains that are derived from the same "parental" clone. For example, a lineage comprising a number of variant clones may be generated from a parental or starting immunoglobulin single variable domain by diversification, site directed mutagenesis, generation of error prone or doped libraries. Suitably binding molecules are generated in a process of affinity maturation. In the present invention, reference is made to "DOM7h-11" which is an anti-SA immunoglobulin single variable domain described in PCT/EP2010/052008 and PCT/EP2010/052007. DOM7h-11-15 is one of the DOM7h-11 lineage derived from DOM7h-11 parental clone, as described herein.
[0046] In the instant application, the term "prevention" and "preventing" involves administration of the protective composition prior to the induction of the disease or condition. "Treatment" and "treating" involves administration of the protective composition after disease or condition symptoms become manifest. "Suppression" or "suppressing" refers to administration of the composition after an inductive event, but prior to the clinical appearance of the disease or condition.
[0047] As used herein, the term "dose" refers to the quantity of ligand administered to a subject all at one time (unit dose), or in two or more administrations over a defined time interval. For example, dose can refer to the quantity of ligand (e.g., ligand comprising an immunoglobulin single variable domain that binds target antigen) administered to a subject over the course of one day (24 hours) (daily dose), two days, one week, two weeks, three weeks or one or more months (e.g., by a single administration, or by two or more administrations). The interval between doses can be any desired amount of time. The term "pharmaceutically effective" when referring to a dose means sufficient amount of the ligand, domain or pharmaceutically active agent to provide the desired effect. The amount that is "effective" will vary from subject to subject, depending on the age and general condition of the individual, the particular drug or pharmaceutically active agent and the like. Thus, it is not always possible to specify an exact "effective" amount applicable for all patients. However, an appropriate "effective" dose in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
[0048] Methods for pharmacokinetic analysis and determination of ligand (e.g., single variable domain, fusion protein or multi-specific ligand) half-life will be familiar to those skilled in the art. Details may be found in Kenneth, A et al: Chemical Stability of Pharmaceuticals: A Handbook for Pharmacists and in Peters et al, Pharmacokinetc analysis: A Practical Approach (1996). Reference is also made to "Pharmacokinetics", M Gibaldi & D Perron, published by Marcel Dekker, 2nd Rev. ex edition (1982), which describes pharmacokinetic parameters such as t alpha and t beta half lives and area under the curve (AUC). Optionally, all pharmacokinetic parameters and values quoted herein are to be read as being values in a human. Optionally, all pharmacokinetic parameters and values quoted herein are to be read as being values in a mouse or rat or Cynomolgus monkey.
[0049] Half lives (t1/2 alpha and t1/2 beta) and AUC can be determined from a curve of serum concentration of ligand against time. The WinNonlin analysis package, e.g. version 5.1 (available from Pharsight Corp., Mountain View, Calif. 94040, USA) can be used, for example, to model the curve. When two-compartment modeling is used, in a first phase (the alpha phase) the ligand is undergoing mainly distribution in the patient, with some elimination. A second phase (beta phase) is the phase when the ligand has been distributed and the serum concentration is decreasing as the ligand is cleared from the patient. The t alpha half life is the half life of the first phase and the t beta half life is the half life of the second phase. Thus, in one embodiment, in the context of the present invention, the variable domain, fusion protein or ligand has a tα half-life in the range of (or of about) 15 minutes or more. In one embodiment, the lower end of the range is (or is about) 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 10 hours, 11 hours or 12 hours. In addition, or alternatively, the variable domain, fusion protein or ligand according to the invention will have a tα half life in the range of up to and including 12 hours (or about 12 hours). In one embodiment, the upper end of the range is (or is about) 11, 10, 9, 8, 7, 6 or 5 hours. An example of a suitable range is (or is about) 1 to 6 hours, 2 to 5 hours or 3 to 4 hours.
[0050] In one embodiment, the present invention provides the variable domain, fusion protein or ligand according to the invention has a tβ half-life in the range of (or of about) 2.5 hours or more. In one embodiment, the lower end of the range is (or is about) 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 10 hours, 11 hours, or 12 hours. In addition, or alternatively, the tβ half-life is (or is about) up to and including 21 or 25 days. In one embodiment, the upper end of the range is (or is about) 12 hours, 24 hours, 2 days, 3 days, 5 days, 10 days, 15 days, 19 days, 20 days, 21 days or 22 days. For example, the variable domain, fusion protein or ligand according to the invention will have a tβ half life in the range 12 to 60 hours (or about 12 to 60 hours). In a further embodiment, it will be in the range 12 to 48 hours (or about 12 to 48 hours). In a further embodiment still, it will be in the range 12 to 26 hours (or about 12 to 26 hours).
[0051] As an alternative to using two-compartment modeling, the skilled person will be familiar with the use of non-compartmental modeling, which can be used to determine terminal half-lives (in this respect, the term "terminal half-life" as used herein means a terminal half-life determined using non-compartmental modeling). The WinNonlin analysis package, e.g. version 5.1 (available from Pharsight Corp., Mountain View, Calif. 94040, USA) can be used, for example, to model the curve in this way. In this instance, in one embodiment the single variable domain, fusion protein or ligand has a terminal half life of at least (or at least about) 8 hours, 10 hours, 12 hours, 15 hours, 28 hours, 20 hours, 1 day, 2 days, 3 days, 7 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days or 25 days. In one embodiment, the upper end of this range is (or is about) 24 hours, 48 hours, 60 hours or 72 hours or 120 hours. For example, the terminal half-life is (or is about) from 8 hours to 60 hours, or 8 hours to 48 hours or 12 to 120 hours, e.g., in man.
[0052] In addition, or alternatively to the above criteria, the variable domain, fusion protein or ligand according to the invention has an AUC value (area under the curve) in the range of (or of about) 1 mgmin/ml or more. In one embodiment, the lower end of the range is (or is about) 5, 10, 15, 20, 30, 100, 200 or 300 mgmin/ml. In addition, or alternatively, the variable domain, fusion protein or ligand according to the invention has an AUC in the range of (or of about) up to 600 mgmin/ml. In one embodiment, the upper end of the range is (or is about) 500, 400, 300, 200, 150, 100, 75 or 50 mgmin/ml. Advantageously the variable domain, fusion protein or ligand will have an AUC in (or about in) the range selected from the group consisting of the following: 15 to 150 mgmin/ml, 15 to 100 mgmin/ml, 15 to 75 mgmin/ml, and 15 to 50 mgmin/ml.
[0053] "Surface Plasmon Resonance": Competition assays can be used to determine if a specific antigen or epitope, such as human serum albumin, competes with another antigen or epitope, such as Cynomolgus serum albumin, for binding to a serum albumin binding ligand described herein, such as a specific dAb. Similarly competition assays can be used to determine if a first ligand such as dAb, competes with a second ligand such as a dAb for binding to a target antigen or epitope. The term "competes" as used herein refers to substance, such as a molecule, compound, preferably a protein, which is able to interfere to any extent with the specific binding interaction between two or more molecules. The phrase "does not competitively inhibit" means that substance, such as a molecule, compound, preferably a protein, does not interfere to any measurable or significant extent with the specific binding interaction between two or more molecules. The specific binding interaction between two or more molecules preferably includes the specific binding interaction between a single variable domain and its cognate partner or target. The interfering or competing molecule can be another single variable domain or it can be a molecule that is structurally and/or functionally similar to a cognate partner or target.
[0054] The term "binding moiety" refers to a domain that specifically binds an antigen or epitope independently of a different epitope or antigen binding domain. A binding moiety may be a domain antibody (dAb) or may be a domain which is a derivative of a non-immunoglobulin protein scaffold, e.g., a scaffold selected from the group consisting of CTLA-4, lipocalin, SpA, an adnectin, affibody, an avimer, GroEl, transferrin, GroES and fibronectin, which binds to a ligand other than the natural ligand (in the case of the present invention, the moiety binds serum albumin). See WO2008/096158, which discloses examples of protein scaffolds and methods for selecting antigen or epitope-specific binding domains from repertoires (see Examples 17 to 25). These specific disclosures of WO2008/096158 are expressly incorporated herein by reference as though explicitly written herein and for use with the present invention, and it is contemplated that any part of such disclosure can be incorporated into one or more claims herein).
[0055] In one aspect, the invention provides an anti-serum albumin (SA) immunoglobulin single variable domain variant of DOM7h-11, wherein the variant comprises at least one mutation at position 22, 42 or 91 (numbering according to Kabat) compared to DOM7h-11. In one embodiment, the variant comprises at least one mutation at position 22, 42 or 91 (numbering according to Kabat) compared to DOM7h-11-15. Suitably a variant in accordance with the invention has 1, 2, 3 or up to 8 changes compared to the amino acid sequence of DOM7h-11 or DOM7h-11-15.
[0056] In another aspect, the invention provides an anti-serum albumin (SA) immunoglobulin single variable domain variant of DOM7h-11, wherein the variant comprises at least one mutation in the framework region 3 (FW3) (amino acids 57-88) or complementarity determining region 3 (CDR3) (amino acids 89-97) compared to DOM7h-11, and wherein the variant has 1, 2, 3 or up to 8 changes compared to the amino acid sequence of DOM7h-11. In one embodiment, the variant comprises at least one mutation at these positions compared to DOM7h11-15.
[0057] In one embodiment, the mutations at any of these positions are mutations to residues as exemplified in the Examples section herein. In another embodiment, mutations are to conservative amino acids substitutions of the exemplified residues.
[0058] Conservative amino acid substitutions are well know to the person skilled in the art and are exemplified by the following table:
TABLE-US-00001 Amino Acid Substitution Original Residues Exemplary Substitutions Preferred Substitutions Ala Val, Leu, Ile Val Arg Lys, Gln, Asn Lys Asn Gln Gln Asp Glu Glu Cys Ser, Ala Ser Gln Asn Asn Glu Asp Asp Gly Pro, Ala Ala His Asn, Gln, Lys, Arg Arg Ile Leu, Val, Met, Ala, Phe, Leu Norleucine Leu Norleucine, Ile, Val, Met, Ile Ala, Phe Lys Arg, 1,4 Diamino- Arg butyricAcid, Gln, Asn Met Leu, Phe, Ile Leu Phe Leu, Val, Ile, Ala, Tyr Leu Pro Ala Gly Ser Thr, Ala, Cys Thr Thr Ser Ser Trp Tyr, Phe Tyr Tyr Trp, Phe, Thr, Ser Phe Val Ile, Met, Leu, Phe, Ala, Leu Norleucine
[0059] Conservative amino acid substitutions may also relate to non-naturally occurring amino acid residues, such as peptidomimetics and other reversed or inverted forms of amino acid moieties which may be incorporated by chemical peptide synthesis.
[0060] Thermostability, or thermodynamic stability, is the quality of a substance/protein to resist (ir-)reversible unfolding upon exposure to elevated temperatures.
[0061] A measure of thermostability/thermodynamic stability can be made using Differential scanning calorimetry (DSC). DSC is a thermoanalytical technique in which the difference in the amount of energy or heat required to increase the temperature of a sample and reference are measured as a function of temperature. It can be used to study a wide range of thermal transitions in proteins and is useful for determining the melting temperatures as well as thermodynamic parameters. Briefly, the protein is heated at a constant rate of 180 degrees C./hr (at 1 mg/mL routinely in PBS) and a detectable heat capacity change associated with thermal denaturation measured. The transition midpoint (Tm) is determined, which is described as the temperature where 50% of the protein is in its native conformation and the other 50% is denatured. Here, DSC determines the apparent transition midpoint (appTm) as most of the proteins examined do not fully refold. The higher the Tm or appTm, the more stable the molecule. Software packages such as was Origin' v7.0383 (Origin Lab) can be used to generate Tm values.
[0062] In one embodiment of the invention, improved thermostability means an increased or higher Tm compared to the parent molecule. Suitably the parent molecule is DOM7h-11 or DOM7h-11-15. Suitably "improved" thermostability means a Tm value higher than the Tm value of the parent molecule. Suitably "improved thermostability" means at least 54° C. or at least 55° C. In one embodiment, "improved thermostability" means at least 57° C. In another embodiment, "improved thermostability" means greater than 55° C. or greater than 57° C. Suitably Tm is measured using DSC as described herein.
[0063] Improved thermostability in an immunoglobulin single variable domain is desirable as it provides enhanced stability of an immunoglobulin single variable domain or protein. Importantly, enhanced thermostability gives a measure of the likelihood of a protein being developable such that a product comprising that improved immunoglobulin single variable domain will have good stability throughout the production process and/or a suitable stability/shelf-life. Improved thermostability and exemplary methods for measuring it such as circular dichroism spectroscopy are describe, for example, in van der Sloot et al. Protein Engineering, Design and Selection, 2004, vol. 17, no. 9, p. 673-680 and Demarest et al. J. Mol. Biol. 2004, 335, 41-48.
[0064] The molecular basis for improved or higher thermostability may be a higher specific number of intra-molecule hydrogen- and ionic interactions than found in a non- or less-thermostable variant.
[0065] An immunoglobulin single variable domain that is shown to have improved thermostability may also, as a direct consequence, give a higher initial expression yield from host cell expression systems. This is because improved thermostability may arise from their being a higher number of intra-molecule interactions which may, in turn, lead to a lower level of misfolding and/or faster kinetics of folding during translation or trans-membrane transport.
[0066] In addition, a protein such as an immunoglobulin single variable domain with improved thermostability may display better overall developability as the protein is more likely to be more resistant to down-stream processes such as increased temperatures and pressure as well as extreme pHs and salt conditions when compared to an immunoglobulin single variable domain with a lower thermostability.
[0067] In one embodiment, immunoglobulin single variable domains in accordance with the invention may be used to generate dual or multi-specific compositions or fusion polypeptides. Accordingly, immunoglobulin single variable domains in accordance with the invention may be used in larger constructs. Suitable constructs include fusion proteins between an anti-SA immunoglobulin single variable domain (dAb) and a monoclonal antibody, NCE, protein or polypeptide and so forth. Accordingly, anti-SA immunoglobulin single variable domains in accordance with the invention may be used to construct multi-specific molecules, for example, bi-specific molecules such as dAb-dAb (i.e. two linked immunoglobulin single variable domains in which one is an anti-SA dAb), mAb-dAb or polypeptide-dAb constructs. In these constructs the anti-SA dAb (AlbudAb®) component provides for half-life extension through binding to serum albumin (SA). Suitable mAb-dAbs and methods for generating these constructs are described, for example, in WO2009/068649.
[0068] Choosing an anti-SA immunoglobulin single variable domain with enhanced, improved or increased thermostability may be desirable as a starting point for a molecule that is to be made into a fusion protein as single molecules may lose thermostability properties once they are linked into a bi-specific construct. Accordingly, starting with a moiety with a higher thermostability will enable any loss in thermostability to be taken into account such that after a bi (or multi) specific construct is generated, an overall useful thermostability is maintained.
[0069] In one embodiment, the variant comprises one or more of the following kinetic characteristics:--
[0070] (a) The variant comprises a binding site that specifically binds human SA with a dissociation constant (KD) from (or from about) 0.1 to (or to about) 10000 nM, optionally from (or from about) 1 to (or to about) 6000 nM, as determined by surface plasmon resonance;
[0071] (b) The variant comprises a binding site that specifically binds human SA with an off-rate constant (Kd) from (or from about) 1.5×10-4 to (or to about) 0.1 sec-1, optionally from (or from about) 3×10-4 to (or to about) 0.1 sec-1 as determined by surface plasmon resonance;
[0072] (c) The variant comprises a binding site that specifically binds human SA with an on-rate constant (Ka) from (or from about) 2×106 to (or to about) 1×104M-1 sec-1, optionally from (or from about) 1×106 to (or to about) 2×104M-1 sec-1 as determined by surface plasmon resonance;
[0073] (d) The variant comprises a binding site that specifically binds Cynomolgus monkey SA with a dissociation constant (KD) from (or from about) 0.1 to (or to about) 10000 nM, optionally from (or from about) 1 to (or to about) 6000 nM, as determined by surface plasmon resonance;
[0074] (e) The variant of any preceding claim, wherein the variant comprises a binding site that specifically binds Cynomolgus monkey SA with an off-rate constant (Kd) from (or from about) 1.5×10-4 to (or to about) 0.1 sec-1, optionally from (or from about) 3×10-4 to (or to about) 0.1 sec-1 as determined by surface plasmon resonance;
[0075] (f) The variant of any preceding claim, wherein the variant comprises a binding site that specifically binds Cynomolgus monkey SA with an on-rate constant (Ka) from (or from about) 2×106 to (or to about) 1×104M-1 sec-1, optionally from (or from about) 1×106 to (or to about) 5×103M-1 sec-1 as determined by surface plasmon resonance;
[0076] (g) The variant comprises a binding site that specifically binds rat SA with a dissociation constant (KD) from (or from about) 1 to (or to about) 10000 nM, optionally from (or from about) 20 to (or to about) 6000 nM, as determined by surface plasmon resonance;
[0077] (h) The variant comprises a binding site that specifically binds rat SA with an off-rate constant (Kd) from (or from about) 2×10-3 to (or to about) 0.15 sec-1, optionally from (or from about) 9×10-3 to (or to about) 0.14 sec-1 as determined by surface plasmon resonance;
[0078] (i) The variant comprises a binding site that specifically binds rat SA with an on-rate constant (Ka) from (or from about) 2×106 to (or to about) 1×104M-1 sec-1, optionally from (or from about) 1×106 to (or to about) 3×104M-1 sec-1 as determined by surface plasmon resonance;
[0079] (j) The variant comprises a binding site that specifically binds mouse SA with a dissociation constant (KD) from (or from about) 1 to (or to about) 10000 nM as determined by surface plasmon resonance;
[0080] (k) The variant comprises a binding site that specifically binds mouse SA with an off-rate constant (Kd) from (or from about) 2×10-3 to (or to about) 0.15 sec-1 as determined by surface plasmon resonance; and/or
[0081] (l) The variant comprises a binding site that specifically binds mouse SA with an on-rate constant (Ka) from (or from about) 2×106 to (or to about) 1×104M-1 sec-1, optionally from (or from about) 2×106 to (or to about) 1.5×104 M-1 sec-1 as determined by surface plasmon resonance.
[0082] Optionally, the variant has
[0083] I: a KD according to (a) and (d), a Kd according to (b) and (e), and a Ka according to (c) and (f); or
[0084] II: a KD according to (a) and (g), a Kd according to (b) and (h), and a Ka according to (c) and (i); or
[0085] III: a KD according to (a) and (j), a Kd according to (b) and (k), and a Ka according to (c) and (l); or
[0086] IV: kinetics according to I and II; or
[0087] V: kinetics according to I and III; or
[0088] VI: kinetics according to I, II and III.
[0089] The invention also provides a ligand comprising a variant of any preceding aspect or embodiment of the invention. For example, the ligand can be a dual-specific ligand (see WO04003019 for examples of dual-specific ligands). In one aspect, the invention provides a multispecific ligand comprising an anti-SA variant of any preceding aspect or embodiment of the invention and a binding moiety that specifically binds a target antigen other than SA. The binding moiety can be any binding moiety that specifically binds a target, e.g., the moiety is an antibody, antibody fragment, scFv, Fab, dAb or a binding moiety comprising a non-immunoglobulin protein scaffold. Such moieties are disclosed in detail in WO2008/096158 (see examples 17 to 25, which disclosure is incorporated herein by reference). Examples of non-immunoglobulin scaffolds are CTLA-4, lipocallin, staphylococcal protein A (spA), Affibody®, Avimers®, adnectins, GroEL and fibronectin.
[0090] In one embodiment, a linker is provided between the anti-target binding moiety and the anti-SA single variant, the linker comprising the amino acid sequence AST, optionally ASTSGPS. Alternative linkers are described in WO2007085814 (incorporated herein by reference) and WO2008/096158 (see the passage at page 135, line 12 to page 140, line 14, which disclosure and all sequences of linkers are expressly incorporated herein by reference as though explicitly written herein and for use with the present invention, and it is contemplated that any part of such disclosure can be incorporated into one or more claims herein).
[0091] In one embodiment of the multispecific ligand, the target antigen may be, or be part of, polypeptides, proteins or nucleic acids, which may be naturally occurring or synthetic. In this respect, the ligand of the invention may bind the target antigen and act as an antagonist or agonist (e.g., EPO receptor agonist). One skilled in the art will appreciate that the choice is large and varied. They may be for instance, human or animal proteins, cytokines, cytokine receptors, where cytokine receptors include receptors for cytokines, enzymes, co-factors for enzymes or DNA binding proteins. Suitable cytokines and growth factors include, but are preferably not limited to: ApoE, Apo-SAA, BDNF, Cardiotrophin-1, EGF, EGF receptor, ENA-78, Eotaxin, Eotaxin-2, Exodus-2, EpoR, FGF-acidic, FGF-basic, fibroblast growth factor-10, FLT3 ligand, Fractalkine (CX3C), GDNF, G-CSF, GM-CSF, GF-β1, insulin, IFN-γ, IGF-I, IGF-II, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8 (72 a.a.), IL-8 (77 a.a.), IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18 (IGIF), Inhibin α, Inhibin β, IP-10, keratinocyte growth factor-2 (KGF-2), KGF, Leptin, LIF, Lymphotactin, Mullerian inhibitory substance, monocyte colony inhibitory factor, monocyte attractant protein, M-CSF, MDC (67 a.a.), MDC (69 a.a.), MCP-1 (MCAF), MCP-2, MCP-3, MCP-4, MDC (67 a.a.), MDC (69 a.a.), MIG, MIP-1α, MIP-1β, MIP-3α, MIP-3β, MIP-4, myeloid progenitor inhibitor factor-1 (MPIF-1), NAP-2, Neurturin, Nerve growth factor, β-NGF, NT-3, NT-4, Oncostatin M, PDGF-AA, PDGF-AB, PDGF-BB, PF-4, RANTES, SDF1α, SDF1β, SCF, SCGF, stem cell factor (SCF), TARC, TGF-α, TGF-β, TGF-β2, TGF-β3, tumour necrosis factor (TNF), TNF-α, TNF-β, TNF receptor I, TNF receptor II, TNIL-1, TPO, VEGF, VEGF receptor 1, VEGF receptor 2, VEGF receptor 3, GCP-2, GRO/MGSA, GRO-β, GRO-γ, HCC1, 1-309, HER 1, HER 2, HER 3 and HER 4, CD4, human chemokine receptors CXCR4 or CCR5, non-structural protein type 3 (NS3) from the hepatitis C virus, TNF-alpha, IgE, IFN-gamma, MMP-12, CEA, H. pylori, TB, influenza, Hepatitis E, MMP-12, internalizing receptors that are over-expressed on certain cells, such as the epidermal growth factor receptor (EGFR), ErBb2 receptor on tumor cells, an internalising cellular receptor, LDL receptor, FGF2 receptor, ErbB2 receptor, transferrin receptor, PDGF receptor, VEGF receptor, PsmAr, an extracellular matrix protein, elastin, fibronectin, laminin, a 1-antitrypsin, tissue factor protease inhibitor, PDK1, GSK1, Bad, caspase-9, Forkhead, an antigen of Helicobacter pylori, an antigen of Mycobacterium tuberculosis, and an antigen of influenza virus. It will be appreciated that this list is by no means exhaustive.
[0092] In one embodiment, the multispecific ligand comprises an anti-SA dAb variant of the invention and an anti-TNFR1 binding moiety, e.g., an anti-TNFR1 dAb. Optionally, the ligand has only one anti-TNFR1 binding moiety (e.g., dAb) to reduce the chance of receptor cross-linking.
[0093] In one embodiment, the anti-TNFR1 binding moiety is DOM1h-131-206 disclosed in WO2008149148 (the amino acid sequence of which and the nucleotide sequence of which, as disclosed in that PCT application, are expressly incorporated herein by reference as though explicitly written herein and for use with the present invention, and it is contemplated that any part of such disclosure can be incorporated into one or more claims herein).
[0094] In one embodiment, the anti-TNFR1 binding moiety or dAb is any such moiety or dAb disclosed in co-pending application PCT/EP2010/052005, the disclosure of which is incorporated herein by reference. In one embodiment, the anti-TNFR1 binding moiety comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of DOM1h-574-156, DOM1h-574-72, DOM1h-574-109, DOM1h-574-138, DOM1h-574-162 or DOM1h-574-180 or the amino acid sequence of any anti-TNFR1 dAb disclosed in Table 3.
[0095] In one embodiment, the ligand of the invention is a fusion protein comprising a variant of the invention fused directly or indirectly to one or more polypeptides. For example, the fusion protein can be a "drug fusion" as disclosed in WO2005/118642 (the disclosure of which is incorporated herein by reference), comprising a variant of the invention and a polypeptide drug as defined in that PCT application.
[0096] As used herein, "drug" refers to any compound (e.g., small organic molecule, nucleic acid, polypeptide) that can be administered to an individual to produce a beneficial, therapeutic or diagnostic effect through binding to and/or altering the function of a biological target molecule in the individual. The target molecule can be an endogenous target molecule encoded by the individual's genome (e.g. an enzyme, receptor, growth factor, cytokine encoded by the individual's genome) or an exogenous target molecule encoded by the genome of a pathogen (e.g. an enzyme encoded by the genome of a virus, bacterium, fungus, nematode or other pathogen). Suitable drugs for use in fusion proteins and conjugates comprising an anti-SA dAb variant of the invention are disclosed in WO2005/118642 and WO2006/059106 (the entire disclosures of which are incorporated herein by reference, and including the entire list of specific drugs as though this list were expressly written herein, and it is contemplated that such incorporation provides disclosure of specific drugs for inclusion in claims herein). For example, the drug can be glucagon-like peptide 1 (GLP-1) or a variant, interferon alpha 2b or a variant or exendin-4 or a variant.
[0097] In one embodiment, the invention provides a drug conjugate as defined and disclosed in WO2005/118642 and WO2006/059106, wherein the conjugate comprises a variant of the invention. In one example, the drug is covalently linked to the variant (e.g., the variant and the drug are expressed as part of a single polypeptide). Alternatively, in an example, the drug is non-covalently bonded or associated with the variant. The drug can be covalently or noncovalently bonded to the variant directly or indirectly (e.g., through a suitable linker and/or noncovalent binding of complementary binding partners (e.g., biotin and avidin)). When complementary binding partners are employed, one of the binding partners can be covalently bonded to the drug directly or through a suitable linker moiety, and the complementary binding partner can be covalently bonded to the variant directly or through a suitable linker moiety. When the drug is a polypeptide or peptide, the drug composition can be a fusion protein, wherein the polypeptide or peptide, drug and the polypeptide binding moiety are discrete parts (moieties) of a continuous polypeptide chain. As described herein, the polypeptide binding moieties and polypeptide drug moieties can be directly bonded to each other through a peptide bond, or linked through a suitable amino acid, or peptide or polypeptide linker.
[0098] A ligand which contains one single variable domain (monomer) variant of the invention or more than one single variable domain (multimer, fusion protein, conjugate, and dual specific ligand as defined herein) which specifically binds to serum albumin, can further comprise one or more entities selected from, but preferably not limited to a label, a tag, an additional single variable domain, a dAb, an antibody, an antibody fragment, a marker and a drug. One or more of these entities can be located at either the COOH terminus or at the N terminus or at both the N terminus and the COOH terminus of the ligand comprising the single variable domain, (either immunoglobulin or non-immunoglobulin single variable domain). One or more of these entities can be located at either the COOH terminus, or the N terminus, or both the N terminus and the COOH terminus of the single variable domain which specifically binds serum albumin of the ligand which contains one single variable domain (monomer) or more than one single variable domains (multimer, fusion protein, conjugate, and dual specific ligand as defined herein). Non-limiting examples of tags which can be positioned at one or both of these termini include a HA, his or a myc tag. The entities, including one or more tags, labels and drugs, can be bound to the ligand which contains one single variable domain (monomer) or more than one single variable domain (multimer, fusion protein, conjugate, and dual specific ligand as defined herein), which binds serum albumin, either directly or through linkers as described above.
[0099] An aspect of the invention provides a fusion product, e.g., a fusion protein or fusion with a peptide or conjugate with an NCE (new chemical entity) drug, comprising a polypeptide drug fused or conjugated (for an NCE) to any variant as described above in accordance with the present invention.
[0100] The invention provides a composition comprising a variant, fusion protein, conjugate or ligand of any aspect of the invention and a pharmaceutically acceptable diluent, carrier, excipient or vehicle.
[0101] Also encompassed herein is an isolated nucleic acid encoding any of the variants, fusion proteins, conjugates or ligands described herein, e.g., a ligand which contains one single variable domain (monomer) variant of the invention or more than one single variable domain (e.g., multimer, fusion protein, conjugate, and dual specific ligand as defined herein) variant which specifically binds to serum albumin, or which specifically binds both human serum albumin and at least one non-human serum albumin, or functionally active fragments thereof. Also encompassed herein is a vector and/or an expression vector, a host cell comprising the vector, e.g., a plant or animal cell and/or cell line transformed with a vector, a method of expressing and/or producing one or more variants, fusion proteins or ligands which contains one single variable domain (monomer) variant or more than one single variable domain variants (e.g., multimer, fusion protein, conjugate, and dual specific ligand as defined herein) which specifically binds to serum albumin, or fragment(s) thereof encoded by said vectors, including in some instances culturing the host cell so that the one or more variants, fusion proteins or ligands or fragments thereof are expressed and optionally recovering the ligand which contains one single variable domain (monomer) or more than one single variable domain (e.g., multimer, fusion protein, conjugate, and dual specific ligand as defined herein) which specifically binds to serum albumin, from the host cell culture medium. Also encompassed are methods of contacting a ligand described herein with serum albumin, including serum albumin and/or non-human serum albumin(s), and/or one or more targets other than serum albumin, where the targets include biologically active molecules, and include animal proteins, cytokines as listed above, and include methods where the contacting is in vitro as well as administering any of the variants, fusion proteins or ligands described herein to an individual host animal or cell in vivo and/or ex vivo. Preferably, administering ligands described herein which comprises a single variable domain (immunoglobulin or non-immunoglobulin) directed to serum albumin and/or non-human serum albumin(s), and one or more domains directed to one or more targets other than serum albumin, will increase the half life, including the T beta and/or terminal half life, of the anti-target ligand. Nucleic acid molecules encoding the variants, fusion proteins or single domain containing ligands or fragments thereof, including functional fragments thereof, are contemplated herein. Vectors encoding the nucleic acid molecules, including but preferably not limited to expression vectors, are contemplated herein, as are host cells from a cell line or organism containing one or more of these expression vectors. Also contemplated are methods of producing any variant, fusion protein or ligand, including, but preferably not limited to any of the aforementioned nucleic acids, vectors and host cells.
[0102] An aspect of the invention provides a nucleic acid comprising a nucleotide sequence encoding a variant according to the invention or a multispecific ligand of the invention or fusion protein of the invention.
[0103] An aspect of the invention provides a nucleic acid comprising the nucleotide sequence of a DOM7h-11 variant selected from DOM7h-11-56, DOM7h-11-57, DOM7h-11-65, DOM7h-11-67, DOM7h-11-68, DOM7h-11-69, DOM7h-11-79 and DOM7h-11-80 or a nucleotide sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to said selected sequence.
[0104] An aspect of the invention provides a vector comprising the nucleic acid of the invention. An aspect of the invention provides an isolated host cell comprising the vector.
[0105] Reference is made to WO2008/096158 for details of library vector systems, combining single variable domains, characterization of dual specific ligands, structure of dual specific ligands, scaffolds for use in constructing dual specific ligands, uses of anti-serum albumin dAbs and multispecific ligands and half-life-enhanced ligands, and compositions and formulations of comprising anti-serum albumin dAbs. These disclosures are incorporated herein by reference to provide guidance for use with the present invention, including for variants, ligands, fusion proteins, conjugates, nucleic acids, vectors, hosts and compositions of the present invention.
[0106] While the present invention is described with reference to DOM7h-11 variants, it will be appreciated that analogous mutations into other anti-SA immunoglobulin single variable domain lineages may be envisaged.
Sequences
TABLE-US-00002
[0107] TABLE 1 Amino Acid Sequences of DOM7h-11 Variant dAbs DOM7h-11-12 (SEQ ID NO: 1) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPK LLILFGSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQ AGTHPTTFGQGTKVEIKR DOM7h-11-15 (SEQ ID NO: 2) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPK LLILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQ AGTHPTTFGQGTKVEIKR DOM7h-11-18 (SEQ ID NO: 3) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPK LLIWFGSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYHCAQ AGTHPTTFGQGTKVEIKR DOM7h-11-19 (SEQ ID NO: 4) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPK LLILFGSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQ TGTHPTTFGQGTKVEIKR DOM7h-11-3 (SEQ ID NO: 5) DIQMTQSPSSLSASVGDRVTITCRASRPIGTTLSWYQQKPGKAPK LLILWNSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQ AGTHPTTFGQGTKVEIKR
TABLE-US-00003 TABLE 2 Nucleotide Sequences of DOM7h-11 Variant dAbs DOM7h-11-12 (SEQ ID NO: 6) GACATCCAGA TGACCCAGTC TCCATCCTCC CTGTCTGCAT C TGTAGGAGA CCGTGTCACC ATCACTTGCC GGGCAAGTCG TC CGATTGGG ACGATGTTAA GTTGGTACCA GCAGAAACCA GGG AAAGCCC CTAAGCTCCT GATCTTGTTT GGTTCCCGGT TGCA AAGTGG GGTCCCATCA CGTTTCAGTG GCAGTGGATC TGGGA CAGAT TTCACTCTCA CCATCAGCAG TCTGCAACCT GAAGAT TTTG CTACGTACTA CTGTGCGCAG GCTGGGACGC ATCCTAC GAC GTTCGGCCAA GGGACCAAGG TGGAAATCAA ACGG DOM7h-11-15 (SEQ ID NO: 7) GACATCCAGA TGACCCAGTC TCCATCCTCC CTGTCTGCAT C TGTAGGAGA CCGTGTCACC ATCACTTGCC GGGCAAGTCG TC CGATTGGG ACGATGTTAA GTTGGTACCA GCAGAAACCA GGG AAAGCCC CTAAGCTCCT GATCCTTGCT TTTTCCCGTT TGCA AAGTGG GGTCCCATCA CGTTTCAGTG GCAGTGGATC TGGGA CAGAT TTCACTCTCA CCATCAGCAG TCTGCAACCT GAAGAT TTTG CTACGTACTA CTGCGCGCAG GCTGGGACGC ATCCTAC GAC GTTCGGCCAA GGGACCAAGG TGGAAATCAA ACGG DOM7h-11-18 (SEQ ID NO: 8) GACATCCAGA TGACCCAGTC TCCATCCTCC CTGTCTGCAT C TGTAGGAGA CCGTGTCACC ATCACTTGCC GGGCAAGTCG TC CGATTGGG ACGATGTTAA GTTGGTACCA GCAGAAACCA GGG AAAGCCC CAAAGCTCCT GATCTGGTTT GGTTCCCGGT TGCA AAGTGG GGTCCCATCA CGTTTCAGTG GCAGTGGATC TGGGA CAGAT TTCACTCTCA CCATCAGCAG TCTGCAACCT GAAGAT TTTG CTACGTACCA CTGTGCGCAG GCGGGGACGC ATCCTAC GAC GTTCGGCCAA GGGACCAAGG TGGAAATCAA ACGG DOM7h-11-19 (SEQ ID NO: 9) GACATCCAGA TGACCCAGTC TCCATCCTCC CTGTCTGCAT C TGTAGGAGA CCGTGTCACC ATCACTTGCC GGGCAAGTCG TC CGATTGGG ACGATGTTAA GTTGGTACCA GCAGAAACCA GGG AAAGCCC CTAAGCTCCT GATCTTGTTT GGTTCCCGGT TGCA AAGTGG GGTCCCATCA CGTTTCAGTG GCAGTGGATC TGGGA CGGAT TTCACTCTCA CCATCAGCAG TCTGCAACCT GAAGAT TTTG CTACGTACTA CTGTGCGCAG ACTGGGACGC ATCCCAC GAC GTTCGGCCAA GGGACCAAGG TGGAAATCAA ACGG DOM7h-11-3 (SEQ ID NO: 10) GACATCCAGA TGACCCAGTC TCCATCCTCC CTGTCTGCAT C TGTAGGAGA CCGTGTCACC ATCACTTGCC GGGCAAGTCG TC CGATTGGG ACGACGTTAA GTTGGTACCA GCAGAAACCA GGG AAAGCCC CTAAGCTCCT GATCCTTTGG AATTCCCGTT TGCA AAGTGG GGTCCCATCA CGTTTCAGTG GCAGTGGATC TGGGA CAGAT TTCACTCTCA CCATCAGCAG TCTGCAACCT GAAGAT TTTG CTACGTACTA CTGTGCGCAG GCTGGGACGC ATCCTAC GAC GTTCGGCCAA GGGACCAAGG TGGAAATCAA ACGG
TABLE-US-00004 TABLE 3 Amino Acid Sequences of anti-TNFR1 dAbs >DOM1h-509 (SEQ ID NO: 11) EVQLLESGGGLVQPGGSLRLSCAASGFTFSQYRMHWVRQAPGKSLEWVSSIDTRGSST YYADPVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKAVTMFSPFFDYWGQGTLV TVSS >DOM1h-510 (SEQ ID NO: 12) EVQLLESGGGLVQPGGSLRLSCAASGFTFADYGMRWVRQAPGKGLEWVSSITRTGRVT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKWRNRHGEYLADFDYWGQG TLVTVSS >DOM1h-543 (SEQ ID NO: 13) EVQLLESGGGLVQPGGSLRLSCAASGFTFMRYRMHWVRQAPGKGLEWVSSIDSNGSST YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRTERSPVFDYWGQGTLV TVSS >DOM1h-549 (SEQ ID NO: 14) EVQLLESGGGLVQPGGSLRLSCAASGFTFVDYEMHWVRQAPGKGLEWVSSISESGTTT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKRRFSASTFDYWGQGTLVT VSS >DOM1h-574 (SEQ ID NO: 15) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGGHT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKYTGHWEPFDYWGQGTLVT VSS >DOM1h-574-1 (SEQ ID NO: 16) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGGHT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKYTGRWEPYDYWGQGTLVT VSS >DOM1h-574-2 (SEQ ID NO: 17) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGGHT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-7 (SEQ ID NO: 18) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGGHT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-8 (SEQ ID NO: 19) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTGGHT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-9 (SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGGHT YYADSVKGRFTISRDNSKNTLYMQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-10 (SEQ ID NO: 21) EVQLLESGGGLVQPGGSLRLSCAASGFTFGKYSMGWVRQAPGKDLEWVSQISNTGGHT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-11 (SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGGHT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKYTGRWEPFDHWGQGTLVT VSS >DOM1h-574-12 (SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDHT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-13 (SEQ ID NO: 24) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-14 (SEQ ID NO: 25) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-15 (SEQ ID NO: 26) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDHT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-16 (SEQ ID NO: 27) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-17 (SEQ ID NO: 28) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTGDHT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-18 (SEQ ID NO: 29) EVQLLESGGGLVQPGGSLRLSCAASGFTFGKYSMGWVRQAPGKDLEWVSQISNTGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-19 (SEQ ID NO: 30) EVQLLESGGGLVQPGGSLRLSCAASGFTFGKYSMGWVRQAPGKDLEWVSQISNTGDHT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-25 (SEQ ID NO: 31) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-26 (SEQ ID NO: 32) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFEYWGQGTLVT VSS >DOM1h-574-27 (SEQ ID NO: 33) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWKPFEYWGQGTLVT VSS >DOM1h-574-28 (SEQ ID NO: 34) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-29 (SEQ ID NO: 35) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVT VSS >DOM1h-574-30 (SEQ ID NO: 36) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRR YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAAYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-31 (SEQ ID NO: 37) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFNYWGQGTLVT VSS >DOM1h-574-32 (SEQ ID NO: 38) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-33 (SEQ ID NO: 39) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRT YYADSVKGRFTISRDNSKNSLYLQMNSLRAEDTAVYYCAIYTGRWVPFDNWGQGTLVT VSS >DOM1h-574-35 (SEQ ID NO: 40) EVQLLESGGGLVQPGGSLRLSCAASGFTFITYSMGWVRQAPGKGLEWVSQISNTGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFQYWGQGTLVT VSS >DOM1h-574-36 (SEQ ID NO: 41) EVQLLESGGGLVQPGGSLRLSCAASGFTFGKYSMGWVRQAPGKGLEWVSQISNTGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT
VSS >DOM1h-574-37 (SEQ ID NO: 42) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISNTGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-38 (SEQ ID NO: 43) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRR YYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-39 (SEQ ID NO: 44) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRR YYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-40 (SEQ ID NO: 45) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFKYWGQGTLVT VSS >DOM1h-574-53 (SEQ ID NO: 46) EVQLLESGGGLVQPGGSLRLSCAASGFTFSKYSMGWVRQAPGKGLEWVSQISNTGERR YYADSVKGRFTISRDNPKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFEYWGQGTLVT VSS >DOM1h-574-54 (SEQ ID NO: 47) EVQLLESGGGLVQPGGSLRLSCAASGFTFVNYSMGWVRQAPGKGLEWVSQISNTGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPYEYWGQGTLVT VTS >DOM1h-574-65 (SEQ ID NO: 48) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRR YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-66 (SEQ ID NO: 49) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRR YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWKPFEYWGQGTLVT VSS >DOM1h-574-67 (SEQ ID NO: 50) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRR YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-68 (SEQ ID NO: 51) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRR YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVT VSS >DOM1h-574-69 (SEQ ID NO: 52) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRR YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-70 (SEQ ID NO: 53) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAVYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-71 (SEQ ID NO: 54) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWKPFEYWGQGTLVT VSS >DOM1h-574-72 (SEQ ID NO: 55) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-73 (SEQ ID NO: 56) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVT VSS >DOM1h-574-74 (SEQ ID NO: 57) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-75 (SEQ ID NO: 58) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRR YYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-76 (SEQ ID NO: 59) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRR YYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWKPFEYWGQGTLVT VSS >DOM1h-574-77 (SEQ ID NO: 60) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRR YYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-78 (SEQ ID NO: 61) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRR YYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVT VSS >DOM1h-574-79 (SEQ ID NO: 62) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRR YYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-84 (SEQ ID NO: 63) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRR YYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-85 (SEQ ID NO: 64) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRR YYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWKPFEYWGQGTLVT VSS >DOM1h-574-86 (SEQ ID NO: 65) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRR YYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-87 (SEQ ID NO: 66) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRR YYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVT VSS >DOM1h-574-88 (SEQ ID NO: 67) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRR YYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-90 (SEQ ID NO: 68) EVQLLESGGGLVQPGGSLRLSCAASGFTFLKFSMGWVRQAPGKGLEWVSQIANTGDRR YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-91 (SEQ ID NO: 69) EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISNTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-92 (SEQ ID NO: 70) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTGDRR YYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-93 (SEQ ID NO: 71) EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTGDRR YYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-94 (SEQ ID NO: 72) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRR YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAAYYCAIYTGRWPDFDYWGQGTLVT VSS
>DOM1h-574-95 (SEQ ID NO: 73) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRR YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAAYYCAIYTGRWPDFEYWGQGTLVT VSS >DOM1h-574-96 (SEQ ID NO: 74) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWPDFDYWGQGTLVT VSS >DOM1h-574-97 (SEQ ID NO: 75) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWPDFEYWGQGTLVT VSS >DOM1h-574-98 (SEQ ID NO: 76) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRR YYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWPDFDYWGQGTLVT VSS >DOM1h-574-99 (SEQ ID NO: 77) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRR YYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWPDFEYWGQGTLVT VSS >DOM1h-574-100 (SEQ ID NO: 78) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISAWGDRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-101 (SEQ ID NO: 79) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISDGGQRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-102 (SEQ ID NO: 80) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISDSGYRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-103 (SEQ ID NO: 81) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISDGGTRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-104 (SEQ ID NO: 82) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISDKGTRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-105 (SEQ ID NO: 83) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISETGRRT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-106 (SEQ ID NO: 84) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQINNTGSTT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVT VSS >DOM1h-574-107 (SEQ ID NO: 85) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-108 (SEQ ID NO: 86) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-109 (SEQ ID NO: 87) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-110 (SEQ ID NO: 88) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-111 (SEQ ID NO: 89) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVT VSS >DOM1h-574-112 (SEQ ID NO: 90) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYTHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-113 (SEQ ID NO: 91) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRR YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-114 (SEQ ID NO: 92) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQILNTADRT YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-115 (SEQ ID NO: 93) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRT YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-116 (SEQ ID NO: 94) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRR YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-117 (SEQ ID NO: 95) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRR YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-118 (SEQ ID NO: 96) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAVYTGRWVSFEYWGQGTLVT VSS >DOM1h-574-119 (SEQ ID NO: 97) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCALYTGRWVSFEYWGQGTLVT VSS >DOM1h-574-120 (SEQ ID NO: 98) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAVYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-121 (SEQ ID NO: 99) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCALYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-122 (SEQ ID NO: 100) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTADRR YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-123 (SEQ ID NO: 101) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRR YYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-124 (SEQ ID NO: 102) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRR YYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-125 (SEQ ID NO: 103) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTADRR YYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-126 (SEQ ID NO: 104) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRR
YYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-127 (SEQ ID NO: 105) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRR YYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-128 (SEQ ID NO: 106) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTADRR YYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-129 (SEQ ID NO: 107) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIVNTGDRR YYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-130 (SEQ ID NO: 108) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRR YYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-131 (SEQ ID NO: 109) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-132 (SEQ ID NO: 110) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVT VSS >DOM1h-574-133 (SEQ ID NO: 111) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-134 (SEQ ID NO: 112) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYSHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-135 (SEQ ID NO: 113) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYTHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-137 (SEQ ID NO: 114) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYTDAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-138 (SEQ ID NO: 115) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-139 (SEQ ID NO: 116) EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-140 (SEQ ID NO: 117) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQIADTGDRR YYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-141 (SEQ ID NO: 118) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRR YYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-142 (SEQ ID NO: 119) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTGDRR YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-143 (SEQ ID NO: 120) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTGDRR YYDDAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-144 (SEQ ID NO: 121) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQIADTADRR YYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-145 (SEQ ID NO: 122) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQIADTGDRR YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-146 (SEQ ID NO: 123) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQIADTGDRR YYDDAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-147 (SEQ ID NO: 124) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWGPFVYWGQGTLVT VSS >DOM1h-574-148 (SEQ ID NO: 125) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFAYWGQGTLVT VSS >DOM1h-574-149 (SEQ ID NO: 126) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWGPFQYWGQGTLVT VSS >DOM1h-574-150 (SEQ ID NO: 127) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFQYWGQGTLVT VSS >DOM1h-574-151 (SEQ ID NO: 128) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-152 (SEQ ID NO: 129) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFQYWGQGTLVT VSS >DOM1h-574-153 (SEQ ID NO: 130) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFQYWGQGTLVT VSS >DOM1h-574-154 (SEQ ID NO: 131) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRR YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-155 (SEQ ID NO: 132) EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-156 (SEQ ID NO: 133) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-157 (SEQ ID NO: 134) EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTADRT YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVT VSS >DOM1h-574-158 (SEQ ID NO: 135) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRT YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVT
VSS >DOM1h-574-159 (SEQ ID NO: 136) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRT YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-160 (SEQ ID NO: 137) EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTADRT YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-161 (SEQ ID NO: 138) EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTADRT YYSHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-162 (SEQ ID NO: 139) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRT YYSHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-163 (SEQ ID NO: 140) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRT YYTHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-164 (SEQ ID NO: 141) EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTADRT YYTHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-165 (SEQ ID NO: 142) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-166 (SEQ ID NO: 143) EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-167 (SEQ ID NO: 144) EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTGDRR YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-169 (SEQ ID NO: 145) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIADTADRT YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-170 (SEQ ID NO: 146) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-171 (SEQ ID NO: 147) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIADTADRT YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-172 (SEQ ID NO: 148) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIADTADRT YYDHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-173 (SEQ ID NO: 149) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIADTADRR YYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-174 (SEQ ID NO: 150) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRR YYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-175 (SEQ ID NO: 151) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIADTADRR YYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-176 (SEQ ID NO: 152) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRR YYDHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-177 (SEQ ID NO: 153) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIADTADRR YYDHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-178 (SEQ ID NO: 154) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIADTADRR YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS >DOM1h-574-179 (SEQ ID NO: 155) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRR YYDDAVKGRFTITRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVT VSS >DOM1h-574-180 (SEQ ID NO: 156) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRT YYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVT VSS >DOM1h-574-4 (SEQ ID NO: 157) EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGGHT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKYTGRWEPFEYWGQGTLVT VSS >DOM1h-574-168 (SEQ ID NO: 158) EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTGDRR YYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS
TABLE-US-00005 TABLE 4 Nucleotide sequences of anti-TNFR1 dAbs >DOM1h-509 (SEQ ID NO: 159) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTAGTCAGTATAGGATGCATTGGGTCCGCCA GGCTCCAGGGAAGAGTCTAGAGTGGGTCTCAAGTATTGATACTAGGGGTTCGTCTACA TACTACGCAGACCCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GAAAGCTGTGACGATGTTTTCTCCTTTTTTTGACTACTGGGGTCAGGGAACCCTGGTC ACCGTCTCGAGC >DOM1h-510 (SEQ ID NO: 160) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGCTGATTATGGGATGCGTTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCATCTATTACGCGGACTGGTCGTGTTACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GAAATGGCGGAATCGGCATGGTGAGTATCTTGCTGATTTTGACTACTGGGGTCAGGGA ACCCTGGTCACCGTCTCGAGC >DOM1h-543 (SEQ ID NO: 161) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTATGAGGTATAGGATGCATTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCATCGATTGATTCTAATGGTTCTAGTACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GAAAGATCGTACGGAGCGTTCGCCGGTTTTTGACTACTGGGGTCAGGGAACCCTGGTC ACCGTCTCGAGC >DOM1h-549 (SEQ ID NO: 162) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTGCAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTGATTATGAGATGCATTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCATCTATTAGTGAGAGTGGTACGACGACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GAAACGTCGTTTTTCTGCTTCTACGTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574 (SEQ ID NO: 163) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GAAATATACGGGTCATTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-1 (SEQ ID NO: 164) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GAAATATACGGGTCGTTGGGAGCCTTATGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-2 (SEQ ID NO: 165) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GAAATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-4 (SEQ ID NO: 166) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GAAATATACGGGTCGTTGGGAGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-180 (SEQ ID NO: 167) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-7 (SEQ ID NO: 168) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-8 (SEQ ID NO: 169) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGATGGGTCCGCCA GGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACA GTCTCGAGC >DOM1h-574-9 (SEQ ID NO: 170) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATATCCCGCGACAATTCCAAGAACA CGCTGTATATGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-10 (SEQ ID NO: 171) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGGTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGATCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-11 (SEQ ID NO: 172) GAGGTGCAGCTGTTGGAGTCAGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GAAATATACGGGTCGTTGGGAGCCTTTTGACCACTGGGGTCAGGGGACCCTGGTCACC GTCTCGAGC >DOM1h-574-12 (SEQ ID NO: 173) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCATACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GAAATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-13 (SEQ ID NO: 174) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA
GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GAAATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-14 (SEQ ID NO: 175) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-15 (SEQ ID NO: 176) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCATACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-16 (SEQ ID NO: 177) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGATGGGTCCGCCA GGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACA GTCTCGAGC >DOM1h-574-17 (SEQ ID NO: 178) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGATGGGTCCGCCA GGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCATACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACA GTCTCGAGC >DOM1h-574-18 (SEQ ID NO: 179) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGGTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGATCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-19 (SEQ ID NO: 180) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGGTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGATCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCATACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-25 (SEQ ID NO: 181) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-26 (SEQ ID NO: 182) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-27 (SEQ ID NO: 183) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCGGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGAAGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-28 (SEQ ID NO: 184) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-29 (SEQ ID NO: 185) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-30 (SEQ ID NO: 186) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGA TACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGCATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-31 (SEQ ID NO: 187) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTAACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-32 (SEQ ID NO: 188) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-33 (SEQ ID NO: 189) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACT CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGTGCCTTTTGACAACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC
>DOM1h-574-35 (SEQ ID NO: 190) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTATTACGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTCAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-36 (SEQ ID NO: 191) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGGTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCGGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-37 (SEQ ID NO: 192) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAAGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-38 (SEQ ID NO: 193) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGA TACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-39 (SEQ ID NO: 194) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTAGA TACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-40 (SEQ ID NO: 195) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTAAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-53 (SEQ ID NO: 196) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTAGTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGAGCGTAGA TACTACGCAGACTCAGTGAAGGGCCGGTTCACCATCTCCCGCGACAATCCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGAGCCTTTTGAATACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-54 (SEQ ID NO: 197) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAACTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACA TACTACGCGGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTATGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCACGAGC >DOM1h-574-65 (SEQ ID NO: 198) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGA TACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGATAATTCCAAGAACA CACTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-66 (SEQ ID NO: 199) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGA TACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGAAGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-67 (SEQ ID NO: 200) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGA TACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-68 (SEQ ID NO: 201) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGA TACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-69 (SEQ ID NO: 202) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGA TACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-70 (SEQ ID NO: 203) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GGTATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-71 (SEQ ID NO: 204) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGAAGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-72 (SEQ ID NO: 205) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC
GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-73 (SEQ ID NO: 206) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-74 (SEQ ID NO: 207) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-75 (SEQ ID NO: 208) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGA TACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-76 (SEQ ID NO: 209) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCCCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGA TACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGAAGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-77 (SEQ ID NO: 210) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGA TACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-78 (SEQ ID NO: 211) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGA TACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-79 (SEQ ID NO: 212) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGA TACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-84 (SEQ ID NO: 213) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTAGA TACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-85 (SEQ ID NO: 214) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTAGA TACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGAAGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-86 (SEQ ID NO: 215) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCCCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTAGA TACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAAGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-87 (SEQ ID NO: 216) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTAGA TACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-88 (SEQ ID NO: 217) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTAGA TACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-90 (SEQ ID NO: 218) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTTTTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGA TACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-91 (SEQ ID NO: 219) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-92 (SEQ ID NO: 220) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGA TACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-93 (SEQ ID NO: 221) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCA
GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGA TACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-94 (SEQ ID NO: 222) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGA TACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGCATATTACTGTGC GATATATACGGGTCGGTGGCCCGACTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-95 (SEQ ID NO: 223) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGA TACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGCATATTACTGTGC GATATATACGGGTCGGTGGCCCGACTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-96 (SEQ ID NO: 224) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGCCCGACTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-97 (SEQ ID NO: 225) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGCCCGACTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-98 (SEQ ID NO: 226) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGA TACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGCCCGACTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-99 (SEQ ID NO: 227) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGA TACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGCCCGACTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-100 (SEQ ID NO: 228) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGATGGGTCCGCCA GGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGGCCTGGGGTGACAGGACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-101 (SEQ ID NO: 229) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGGACGGCGGTCAGAGGACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-102 (SEQ ID NO: 230) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGATGGGTCCGCCA GGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGGACTCCGGTTACCGCACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-103 (SEQ ID NO: 231) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCCAGAGTGGGTCTCACAGATTTCGGACGGGGGTACGCGGACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-104 (SEQ ID NO: 232) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGATGGGTCCGCCA GGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGGACAAGGGTACGCGCACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-105 (SEQ ID NO: 233) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGATGGGTCCGCCA GGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGGAGACCGGTCGCAGGACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-106 (SEQ ID NO: 234) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTAACAATACGGGTTCGACCACA TACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-107 (SEQ ID NO: 235) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCCAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-108 (SEQ ID NO: 236) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCCAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-109
(SEQ ID NO: 237) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-110 (SEQ ID NO: 238) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-111 (SEQ ID NO: 239) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-112 (SEQ ID NO: 240) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACACACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-113 (SEQ ID NO: 241) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGCAGA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-114 (SEQ ID NO: 242) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTTGAATACTGCTGATCGTACA TACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-115 (SEQ ID NO: 243) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-116 (SEQ ID NO: 244) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTAGA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-117 (SEQ ID NO: 245) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTAGA TACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-118 (SEQ ID NO: 246) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GGTATATACTGGGCGTTGGGTGTCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-119 (SEQ ID NO: 247) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GCTATATACTGGGCGTTGGGTGTCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-120 (SEQ ID NO: 248) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTTACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GGTATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-121 (SEQ ID NO: 249) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GCTATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-122 (SEQ ID NO: 250) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACTGCTGATCGTAGA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-123 (SEQ ID NO: 251) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTAGA TACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-124 (SEQ ID NO: 252) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCGGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGCGATCGTAGA TACTACGCACACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC
GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-125 (SEQ ID NO: 253) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACTGCTGATCGTAGA TACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-126 (SEQ ID NO: 254) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGA TACTACGCACACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-127 (SEQ ID NO: 255) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTAGA TACTACGCACACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-128 (SEQ ID NO: 256) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGCTGATCGTAGA TACTACGCACACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-129 (SEQ ID NO: 257) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGTGAATACGGGTGATCGTAGA TACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-130 (SEQ ID NO: 258) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGA TACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-131 (SEQ ID NO: 259) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-132 (SEQ ID NO: 260) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-133 (SEQ ID NO: 261) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-134 (SEQ ID NO: 262) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACTCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-135 (SEQ ID NO: 263) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACACACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-137 (SEQ ID NO: 264) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACACAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-138 (SEQ ID NO: 265) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-139 (SEQ ID NO: 266) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-140 (SEQ ID NO: 267) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACGGGTGATCGTAGA TACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-141 (SEQ ID NO: 268) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTAGA
TACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-142 (SEQ ID NO: 269) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGCC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGA TACTACGATCACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAACCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-143 (SEQ ID NO: 270) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGA TACTACGATGACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-144 (SEQ ID NO: 271) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTAGA TACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-145 (SEQ ID NO: 272) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACGGGTGATCGTAGA TACTACGATCACTCTGTGAAGGGCCGGTTCACTATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-146 (SEQ ID NO: 273) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACGGGTGATCGTAGA TACTACGATGACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-147 (SEQ ID NO: 274) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGGGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-148 (SEQ ID NO: 275) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGTGCCTTTTGCCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-149 (SEQ ID NO: 276) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGGACCTTTTCAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-150 (SEQ ID NO: 277) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTCAGTACTGGGGTCAGGGAACTCTGGTCACC GTCTCGAGC >DOM1h-574-151 (SEQ ID NO: 278) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-152 (SEQ ID NO: 279) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGCGCCTTTTCAGTACTGGGGTCAGGGAACTCTGGTCACC GTCTCGAGC >DOM1h-574-153 (SEQ ID NO: 280) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGTGCCTTTTCAGTACTGGGGTCAGGGCACCCTGGTCACC GTCTCGAGC >DOM1h-574-154 (SEQ ID NO: 281) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACCGGTGATCGTAGA TACTACGATCACTCTGTGAAGGGCCGGTTCACTATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-155 (SEQ ID NO: 282) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-156 (SEQ ID NO: 283) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-157 (SEQ ID NO: 284)
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-158 (SEQ ID NO: 285) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-159 (SEQ ID NO: 286) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-160 (SEQ ID NO: 287) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-161 (SEQ ID NO: 288) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACTCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-162 (SEQ ID NO: 289) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACTCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-163 (SEQ ID NO: 290) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACACACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-164 (SEQ ID NO: 291) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACACACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-165 (SEQ ID NO: 292) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-166 (SEQ ID NO: 293) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-167 (SEQ ID NO: 294) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACCGGTGATCGTAGA TACTACGATCACTCTGTGAAGGGCCGGTTCACTATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-168 (SEQ ID NO: 295) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACCGGTGATCGTAGA TACTACGATCACTCTGTGAAGGGCCGGTTCACTATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-16 9 (SEQ ID NO: 296) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTACA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGCGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-170 (SEQ ID NO: 297) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACA TACTACGCACACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-171 (SEQ ID NO: 298) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTGCAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTACA TACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-172 (SEQ ID NO: 299) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTACA TACTACGATCACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGC GATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC
GTCTCGAGC >DOM1h-574-173 (SEQ ID NO: 300) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTAGA TACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-174 (SEQ ID NO: 301) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTAGA TACTACGCACACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-175 (SEQ ID NO: 302) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTAGA TACTACGCACACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-176 (SEQ ID NO: 303) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTAGA TACTACGATCACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-177 (SEQ ID NO: 304) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTAGA TACTACGATCACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGGACCCTGGTCACC GTCTCGAGC >DOM1h-574-178 (SEQ ID NO: 305) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTAGA TACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC >DOM1h-574-179 (SEQ ID NO: 306) GAGGTGCAGCTGCTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTC TCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCA GGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTAGA TACTACGATGACGCGGTGAAGGGCCGGTTCACCATCACCCGCGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGC GATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC
TABLE-US-00006 TABLE 5 Anti-serum albumin dAb (DOM7h) fusions (used in Rat studies):- DOM7h-14/Exendin-4 fusion DMS number 7138 Amino acid sequence (SEQ ID NO: 307) HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGGGGSGGG GSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQWIGSQLSWYQQKPG KAPKLLIMWRSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCA QGAALPRTFGQGTKVEIKR Nucleotide sequence (SEQ ID NO: 308) CATGGTGAAGGAACATTTACCAGTGACTTGTCAAAACAGATGGAAGAG GAGGCAGTGCGGTTATTTATTGAGTGGCTTAAGAACGGAGGACCAAGT AGCGGGGCACCTCCGCCATCGGGTGGTGGAGGCGGTTCAGGCGGAGGT GGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCC TCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCA AGTCAGTGGATTGGGTCTCAGTTATCTTGGTACCAGCAGAAACCAGGG AAAGCCCCTAAGCTCCTGATCATGTGGCGTTCCTCGTTGCAAAGTGGG GTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTC ACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCT CAGGGTGCGGCGTTGCCTAGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGG DOM7h-14-10/Exendin-4 fusion DMS number 7139 Amino acid sequence (SEQ ID NO: 309) HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGGGGSGGG GSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQWIGSQLSWYQQKPG KAPKLLIMWRSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCA QGLRHPKTFGQGTKVEIKR Nucleotide sequence (SEQ ID NO: 310) CATGGTGAAGGAACATTTACCAGTGACTTGTCAAAACAGATGGAAGAG GAGGCAGTGCGGTTATTTATTGAGTGGCTTAAGAACGGAGGACCAAGT AGCGGGGCACCTCCGCCATCGGGTGGTGGAGGCGGTTCAGGCGGAGGT GGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCC TCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCA AGTCAGTGGATTGGGTCTCAGTTATCTTGGTACCAGCAGAAACCAGGG AAAGCCCCTAAGCTCCTGATCATGTGGCGTTCCTCGTTGCAAAGTGGG GTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTC ACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCT CAGGGTTTGAGGCATCCTAAGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGG DOM7h-14-18/Exendin-4 fusion DMS number 7140 Amino acid sequence (SEQ ID NO: 311) HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGGGGSGGG GSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQWIGSQLSWYQQKPG KAPKLLIMWRSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCA QGLMKPMTFGQGTKVEIKR Nucleotide sequence (SEQ ID NO: 312) CATGGTGAAGGAACATTTACCAGTGACTTGTCAAAACAGATGGAAGAG GAGGCAGTGCGGTTATTTATTGAGTGGCTTAAGAACGGAGGACCAAGT AGCGGGGCACCTCCGCCATCGGGTGGTGGAGGCGGTTCAGGCGGAGGT GGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCC TCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCA AGTCAGTGGATTGGGTCTCAGTTATCTTGGTACCAGCAGAAACCAGGG AAAGCCCCTAAGCTCCTGATCATGTGGCGTTCCTCGTTGCAAAGTGGG GTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTC ACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCT CAGGGTCTTATGAAGCCTATGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGG DOM7h-14-19/Exendin-4 fusion DMS number 7141 Amino acid sequence (SEQ ID NO: 313) HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGGGGSGGG GSGGGGSDIQMTQSPSSLSASVGDRVTISCRASQWIGSQLSWYQQKPG EAPKLLIMWRSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCA QGAALPRTFGQGTKVEIKR Nucleotide sequence (SEQ ID NO: 314) CATGGTGAAGGAACATTTACCAGTGACTTGTCAAAACAGATGGAAGAG GAGGCAGTGCGGTTATTTATTGAGTGGCTTAAGAACGGAGGACCAAGT AGCGGGGCACCTCCGCCATCGGGTGGTGGAGGCGGTTCAGGCGGAGGT GGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCC TCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCTCTTGCCGGGCA AGTCAGTGGATTGGGTCTCAGTTATCTTGGTACCAGCAGAAACCAGGG GAAGCCCCTAAGCTCCTGATCATGTGGCGTTCCTCGTTGCAAAGTGGG GTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTC ACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCT CAGGGTGCGGCGTTGCCTAGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGG DOM7h-11/Exendin-4 fusion DMS number 7142 Amino acid sequence (SEQ ID NO: 315) HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGGGGSGGG GSGGGGSDIQMTQSPSSLSASVGDRVTITCRASRPIGTTLSWYQQKPG KAPKLLIWFGSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCA QAGTHPTTFGQGTKVEIKR Nucleotide sequence (SEQ ID NO: 316) CATGGTGAAGGAACATTTACCAGTGACTTGTCAAAACAGATGGAAGAG GAGGCAGTGCGGTTATTTATTGAGTGGCTTAAGAACGGAGGACCAAGT AGCGGGGCACCTCCGCCATCGGGTGGTGGAGGCGGTTCAGGCGGAGGT GGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCC TCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCA AGTCGTCCGATTGGGACGACGTTAAGTTGGTACCAGCAGAAACCAGGG AAAGCCCCTAAGCTCCTGATCTGGTTTGGTTCCCGGTTGCAAAGTGGG GTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTC ACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCG CAGGCTGGGACGCATCCTACGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGG DOM7h-11-12/Exendin-4 fusion DMS number 7147 Amino acid sequence (SEQ ID NO: 317) HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGGGGSGGG GSGGGGSDIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPG KAPKLLILFGSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCA QAGTHPTTFGQGTKVEIKR Nucleotide sequence (SEQ ID NO: 318) CATGGTGAAGGAACATTTACCAGTGACTTGTCAAAACAGATGGAAGAG GAGGCAGTGCGGTTATTTATTGAGTGGCTTAAGAACGGAGGACCAAGT AGCGGGGCACCTCCGCCATCGGGTGGTGGAGGCGGTTCAGGCGGAGGT GGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCC TCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCA AGTCGTCCGATTGGGACGATGTTAAGTTGGTACCAGCAGAAACCAGGG AAAGCCCCTAAGCTCCTGATCTTGTTTGGTTCCCGGTTGCAAAGTGGG GTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTC ACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCG CAGGCTGGGACGCATCCTACGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGG DOM7h-11-15/Exendin-4 fusion DMS number 7143 Amino acid sequence (SEQ ID NO: 319) HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGGGGSGGG GSGGGGSDIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPG KAPKLLILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCA QAGTHPTTFGQGTKVEIKR Nucleotide sequence (SEQ ID NO: 320) CATGGTGAAGGAACATTTACCAGTGACTTGTCAAAACAGATGGAAGAG GAGGCAGTGCGGTTATTTATTGAGTGGCTTAAGAACGGAGGACCAAGT AGCGGGGCACCTCCGCCATCGGGTGGTGGAGGCGGTTCAGGCGGAGGT GGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCC TCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCA AGTCGTCCGATTGGGACGATGTTAAGTTGGTACCAGCAGAAACCAGGG AAAGCCCCTAAGCTCCTGATCCTTGCTTTTTCCCGTTTGCAAAGTGGG GTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTC ACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGCGCG CAGGCTGGGACGCATCCTACGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGG
DOM7h14-10/G4SC-NCE fusion Amino acid sequence (SEQ ID NO: 321) encoding DOM7h14-10/G4SC DIQMTQSPSSLSASVGDRVTITCRASQW1GSQLSWYQQKPGKAPKLLI MWRSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQGLRHPK TFGQGTKVEIKRGGGGSC The C-terminal cysteine can be linked to a new chemical entity (pharmaceutical chemical compound, NCE), eg using maleimide linkage. Nucleotide sequence (SEQ ID NO: 322) encoding DOM7h14-10/G4SC GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA GACCGTGTCACCATCACTTGCCGGGCAAGTCAGTGGATTGGGTCTCAG TTATCTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATC ATGTGGCGTTCCTCGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGC AGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCT GAAGATTTTGCTACGTACTACTGTGCTCAGGGTTTGAGGCATCCTAAG ACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGGGGTGGCGGAGGG GGTTCCTGT DOM7h14-10/TVAAPSC fusion Amino acid sequence (SEQ ID NO: 323) DIQMTQSPSSLSASVGDRVTITCRASQWIGSQLSWYQQKPGKAPKLLI MWRSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQGLRHPK TFGQGTKVEIKRTVAAPSC The C-terminal cysteine can be linked to a new chemical entity (pharmaceutical chemical compound, NCE), eg using maleimide linkage. Nucleotide sequence (SEQ ID NO: 324) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA GACCGTGTCACCATCACTTGCCGGGCAAGTCAGTGGATTGGGTCTCAG TTATCTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATC ATGTGGCGTTCCTCGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGC AGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCT GAAGATTTTGCTACGTACTACTGTGCTCAGGGTTTGAGGCATCCTAAG ACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGGACCGTCGCTGCT CCATCTTGT (used in mouse studies):- DOM7h-11/DOM1m-21-23 fusion DMS number 5515 Amino acid sequence (SEQ ID NO: 325) EVQLLESGGGLVQPGGSLRLSCAASGFTFNRYSMGWLRQAPGKGLEWV SRIDSYGRGTYYEDPVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYYC AKISQFGSNAFDYWGQGTQVTVSSASTSGPSDIQMTQSPSSLSASVGD RVTITCRASRPIGTTLSWYQQKPGKAPKLLIWFGSRLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKVEIKR Amino acid plus nucleotide plus myc tag sequence (SEQ ID NO: 326) EVQLLESGGGLVQPGGSLRLSCAASGFTFNRYSMGWLRQAPGKGLEWV SRIDSYGRGTYYEDPVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYYC AKISQFGSNAFDYWGQGTQVTVSSASTSGPSDIQMTQSPSSLSASVGD RVTITCRASRPIGTTLSWYQQKPGKAPKLLIWFGSRLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKVEIKRAAAEQ KLISEEDLN Nucleotide sequence (SEQ ID NO: 327) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGG TCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAATAGGTAT AGTATGGGGTGGCTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTC TCACGGATTGATTCTTATGGTCGTGGTACATACTACGAAGACCCCGTG AAGGGCCGGTTCAGCATCTCCCGCGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCCGTATATTACTGT GCGAAAATTTCTCAGTTTGGGTCAAATGCGTTTGACTACTGGGGTCAG GGAACCCAGGTCACCGTCTCGAGCGCTAGCACCAGTGGTCCATCGGAC ATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGAC CGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGACGTTA AGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTGG TTTGGTTCCCGGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGT GGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAA GATTTTGCTACGTACTACTGTGCGCAGGCTGGGACGCATCCTACGACG TTCGGCCAAGGGACCAAGGTGGAAATCAAACGG Nucleotide plus myc tag sequence (SEQ ID NO: 328) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGG TCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAATAGGTAT AGTATGGGGTGGCTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTC TCACGGATTGATTCTTATGGTCGTGGTACATACTACGAAGACCCCGTG AAGGGCCGGTTCAGCATCTCCCGCGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCCGTATATTACTGT GCGAAAATTTCTCAGTTTGGGTCAAATGCGTTTGACTACTGGGGTCAG GGAACCCAGGTCACCGTCTCGAGCGCTAGCACCAGTGGTCCATCGGAC ATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGAC CGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGACGTTA AGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTGG TTTGGTTCCCGGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGT GGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAA GATTTTGCTACGTACTACTGTGCGCAGGCTGGGACGCATCCTACGACG TTCGGCCAAGGGACCAAGGTGGAAATCAAACGGGCGGCCGCAGAACAA AAACTCATCTCAGAAGAGGATCTGAATTAA DOM7h-11-12/DOM1m-21-23 fusion DMS number 5516 Amino acid sequence (SEQ ID NO: 329) EVQLLESGGGLVQPGGSLRLSCAASGFTFNRYSMGWLRQAPGKGLEWV SRIDSYGRGTYYEDPVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYYC AKISQFGSNAFDYWGQGTQVTVSSASTSGPSDIQMTQSPSSLSASVGD RVTITCRASRPIGTMLSWYQQKPGKAPKLLILFGSRLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKVEIKR Amino acid plus nucleotide plus myc tag sequence (SEQ ID NO: 330) EVQLLESGGGLVQPGGSLRLSCAASGFTFNRYSMGWLRQAPGKGLEWV SRIDSYGRGTYYEDPVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYYC AKISQFGSNAFDYWGQGTQVTVSSASTSGPSDIQMTQSPSSLSASVGD RVTITCRASRPIGTMLSWYQQKPGKAPKLLILFGSRLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKVEIKRAAAEQ KLISEEDLN Nucleotide sequence (SEQ ID NO: 331) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGG TCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAATAGGTAT AGTATGGGGTGGCTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTC TCACGGATTGATTCTTATGGTCGTGGTACATACTACGAAGACCCCGTG AAGGGCCGGTTCAGCATCTCCCGCGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCCGTATATTACTGT GCGAAAATTTCTCAGTTTGGGTCAAATGCGTTTGACTACTGGGGTCAG GGAACCCAGGTCACCGTCTCGAGCGCTAGCACCAGTGGTCCATCGGAC ATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGAC CGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTTA AGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTG TTTGGTTCCCGGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGT GGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAA GATTTTGCTACGTACTACTGTGCGCAGGCTGGGACGCATCCTACGACG TTCGGCCAAGGGACCAAGGTGGAAATCAAACGG Nucleotide plus myc tag sequence (SEQ ID NO: 332) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGG TCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAATAGGTAT AGTATGGGGTGGCTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTC TCACGGATTGATTCTTATGGTCGTGGTACATACTACGAAGACCCCGTG AAGGGCCGGTTCAGCATCTCCCGCGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCCGTATATTACTGT GCGAAAATTTCTCAGTTTGGGTCAAATGCGTTTGACTACTGGGGTCAG GGAACCCAGGTCACCGTCTCGAGCGCTAGCACCAGTGGTCCATCGGAC ATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGAC CGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTTA AGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTG TTTGGTTCCCGGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGT GGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAA GATTTTGCTACGTACTACTGTGCGCAGGCTGGGACGCATCCTACGACG TTCGGCCAAGGGACCAAGGTGGAAATCAAACGGGCGGCCGCAGAACAA AAACTCATCTCAGAAGAGGATCTGAATTAA DOM7h-11-15/DOM1m-21-23 fusion DMS number 5517 Amino acid sequence (SEQ ID NO: 333)
EVQLLESGGGLVQPGGSLRLSCAASGFTFNRYSMGWLRQAPGKGLEWV SRIDSYGRGTYYEDPVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYYC AKISQFGSNAFDYWGQGTQVTVSSASTSGPSDIQMTQSPSSLSASVGD RVTITCRASRPIGTMLSWYQQKPGKAPKLLILAFSRLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKVEIKR Amino acid plus nucleotide plus myc tag sequence (SEQ ID NO: 334) EVQLLESGGGLVQPGGSLRLSCAASGFTFNRYSMGWLRQAPGKGLEWV SRIDSYGRGTYYEDPVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYYC AKISQFGSNAFDYWGQGTQVTVSSASTSGPSDIQMTQSPSSLSASVGD RVTITCRASRPIGTMLSWYQQKPGKAPKLLILAFSRLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKVEIKRAAAEQ KLISEEDLN Nucleotide sequence (SEQ ID NO: 335) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGG TCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAATAGGTAT AGTATGGGGTGGCTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTC TCACGGATTGATTCTTATGGTCGTGGTACATACTACGAAGACCCCGTG AAGGGCCGGTTCAGCATCTCCCGCGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCCGTATATTACTGT GCGAAAATTTCTCAGTTTGGGTCAAATGCGTTTGACTACTGGGGTCAG GGAACCCAGGTCACCGTCTCGAGCGCTAGCACCAGTGGTCCATCGGAC ATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGAC CGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTTA AGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTT GCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGT GGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAA GATTTTGCTACGTACTACTGCGCGCAGGCTGGGACGCATCCTACGACG TTCGGCCAAGGGACCAAGGTGGAAATCAAACGG Nucleotide plus myc tag sequence (SEQ ID NO: 336) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGG TCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAATAGGTAT AGTATGGGGTGGCTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTC TCACGGATTGATTCTTATGGTCGTGGTACATACTACGAAGACCCCGTG AAGGGCCGGTTCAGCATCTCCCGCGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCCGTATATTACTGT GCGAAAATTTCTCAGTTTGGGTCAAATGCGTTTGACTACTGGGGTCAG GGAACCCAGGTCACCGTCTCGAGCGCTAGCACCAGTGGTCCATCGGAC ATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGAC CGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTTA AGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTT AGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTG GCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCCAACCTGAA CGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGGGCGGCCGCAGAAC GATTTTGCTACGTACTACTGCGCGCAGGCTGGGACGCATCCTACGAAA AAACTCATCTCAGAAGAGGATCTGAATTAA
[0108] Where a myc-tagged molecule is indicated in this table, this was the version used in PK studies in the examples. Where no myc-tagged sequences are given, the PK studies in the examples were not done with myc-tagged material, ie, the studies were done with the non-tagged constructs shown.
EXEMPLIFICATION
[0109] All numbering in the experimental section is according to Kabat (Kabat, E. A. National Institutes of Health (US) & Columbia University. Sequences of proteins of immunological interest, edn 5 (US Dept. Of Health and Human Services Public Health Service, National Institutes of Health, Bethesda, Md., 1991)).
[0110] Derivation of DOM7h-11 variants is described.
Example 1
Vk Affinity Maturation
Selections:
[0111] HSA (Human Serum Albumin) and RSA (Rat Serum Albumin) antigens were obtained from Sigma (essentially fatty acid free, ˜99% (agarose gel electrophoresis), lyophilized powder Cat. No. A3782 and A6414 respectively)
[0112] Biotinylated products of above two antigens were made by using EZ Link Sulfo-NHS-SS-Biotin (Pierce, Cat. No. 21331). Free biotin reagent was removed by passing the samples twice through PD10 desalting column followed by overnight dialysis against 1000× excess volume of PBS at 4° C. Resulting product was tested by mass spec and 1-2 biotins per molecule were observed.
Affinity Maturation Libraries:
[0113] Both error-prone and CDR libraries were created using DOM7h-11 and DOM7h-14 parental dAbs (see WO2008/096158 for the sequences of DOM7h-11 and DOM7h-14). The CDR libraries were generated in the pDOM4 vector and the error prone libraries were generated in the pDOM33 vector (to allow for selection with or without protease treatment). Vector pDOM4, is a derivative of the Fd phage vector in which the gene III signal peptide sequence is replaced with the yeast glycolipid anchored surface protein (GAS) signal peptide. It also contains a c-myc tag between the leader sequence and gene III, which puts the gene III back in frame. This leader sequence functions well both in phage display vectors but also in other prokaryotic expression vectors and can be universally used. pDOM33 is a modified version of the pDOM4 vector where the the c-myc tag has been removed which renders the dAb-phage fusion resistant to the protease trypsin. This allows the use of trypsin within the phage selection to select for dAbs that are more protease stable (see WO2008149143).
[0114] For error-prone maturation libraries, plasmid DNA encoding the dAb to be matured was amplified by PCR, using the GENEMORPH® II RANDOM MUTAGENESIS KIT (random, unique mutagenesis kit, Stratagene). The product was digested with Sal I and Not I and used in a ligation reaction with cut phage vector pDOM33. For the CDR libraries, PCR reactions were performed using degenerate oligonucleotides containing NNK or NNS codons to diversify the required positions in the dAb to be affinity matured. Assembly PCR was then used to generate a full length diversified insert. The insert was digested with Sal I and Not I and used in a ligation reaction with pDOM4 for mutagenesis of multiple residues and pDOM5 for mutagenesis of single residues. The pDOM5 vector is a pUC119-based expression vector where protein expression is driven by the LacZ promoter. A GAS 1 leader sequence (see WO 2005/093074) ensures secretion of isolated, soluble dAbs into the periplasm and culture supernatant of E. coli. dAbs are cloned SalI/NotI in this vector, which appends a myc tag at the C-terminus of the dAb. This protocol using SalI and Not I results in inclusion of an ST amino acid sequence at the N-terminus.
[0115] The ligation produced by either method was then used to transform E. coli strain TB1 by electroporation and the transformed cells plated on 2xTY agar containing 15 μg/ml tetracycline, yielding library sizes of >5×107 clones.
[0116] The error-prone libraries had the following average mutation rate and size: DOM7h-11 (2.5 mutations per dAb), size: 6.1×108, DOM7h-14 (2.9 mutations per dAb), size: 5.4×108.
[0117] Each CDR library has four amino acid diversity. Two libraries were generated for each of CDRs 1 and 3, and one library for CDR2. The positions diversified within each library are as follows (amino acids based on VK dummy DPK9 sequence):
TABLE-US-00007 Library size DOM7h-11 DOM7h-14 1 - Q27, S28, S30, S31 (CDR1) 8.8 × 107 5.8 × 107 2 - S30, S31, Y32, N34 (CDR1) 4.6 × 108 4.2 × 108 3 - Y49, A50, A51, S53 (CDR2) 3.9 × 108 2.4 × 108 4 - Q89, S91, Y92, S93 (CDR3) 1.8 × 108 2.5 × 108 5 - Y92, Y93, T94, N96 (CDR3) 4.0 × 108 3.3 × 108
Example 2
Selection Strategies
[0118] 1) Three Phage Selection Strategies were Adopted for Vic AlbudAb® (Anti-Serum Albumin dAb) Affinity Maturation:Selections Against HSA Only:
[0119] Three rounds of selection against HSA were carried out. The error prone libraries and each CDR library were selected as an individual pool in all rounds. The first round of selection was performed against HSA passively coated onto an immunotube at 1 mg/ml. Round 2 was performed against 100 nM HSA and round 3 against 10 nM (CDR selections) or 20 or 100 nM (Error prone selections) HSA, both as soluble selections followed by a fourth round of selection with the error prone libraries against 1.5 nM HSA as a soluble selection. The error prone libraries were eluted with 0.1M glycine pH 2.0 before neutralisation with 1M Tris pH 8.0 and the CDR libraries were eluted with 1 mg/ml trypsin before infection into log phase TG1 cells. The third round of each selection was subcloned into pDOM5 for screening. Soluble selections used biotinylated HSA.
[0120] 2) Trypsin Selections Against HSA:
[0121] In order to select dAbs with increased protease resistance compared to the parental clone and with potentially improved biophysical properties, trypsin was used in phage selections (see WO2008149143). Four rounds of selection were preformed against HSA. The first round of selection of error prone libraries was performed against passively coated HSA at 1 mg/ml without trypsin; the second round against passively coated HSA at 1 mg/ml with 20 μg/ml trypsin for 1 hour at 37° C.; the third round selection was performed by soluble selection using biotinylated HSA against 100 nM HSA with 20 μg/ml or 100 μg/ml trypsin for 1 hour at 37° C. The final round of selection was performed by soluble selection using biotinylated HSA against 100 nM HSA with 100 μg/ml trypsin overnight at 37° C.
[0122] 3) Cross-Over Selections Against HSA (Round 1) and RSA (Rounds 2-4):
[0123] The first round selection was carried out against 1 mg/ml passively coated HSA or 1 μM HSA (soluble selection), followed by a further three rounds of soluble selections against biotinylated RSA at concentrations of 1 μM for round 1, 100 nm for round 2 and 20 nM, 10 nM or 1 nM for round 3.
Screening Strategy and Affinity Determination:
[0124] In each case after selection a pool of phage DNA from the appropriate round of selection is prepared using a QIAfilter midiprep kit (Qiagen), the DNA is digested using the restriction enzymes SalI and Not1 and the enriched V genes are ligated into the corresponding sites in pDOM5 the soluble expression vector which expresses the dAb with a myc tag (see PCT/EP2008/067789). The ligated DNA is used to electro-transform E. coli HB 2151 cells which are then grown overnight on agar plates containing the antibiotic carbenicillin. The resulting colonies are individually assessed for antigen binding. In each case at least 96 clones were tested for binding to HSA, CSA (Cynomolgus monkey Serum Albumin), MSA (mouse serum albumin) and RSA by BIAcore® (surface plasmon resonance). MSA antigen was obtained from Sigma (essentially fatty acid free, ˜99% (agarose gel electrophoresis), lyophilized powder Cat. No. A3559) and CSA was purified from Cynomolgus serum albumin using prometic blue resin (Amersham). Soluble dAb fragments were produced in bacterial culture in ONEX culture media (Novagen) overnight at 37° C. in 96 well plates. The culture supernatant containing soluble dAb was centrifuged and analysed by BIAcore for binding to high density HSA, CSA, MSA and RSA CM5 chips. Clones were found to bind to all these species of serum albumin by off-rate screening. The clones were sequenced revealing unique dAb sequences. The minimum identity to parent (at the amino acid level) of the clones selected was 97.2% (DOM7h-11-3: 97.2%, DOM7h-11-12: 98.2%, DOM7h11-15: 96.3%, DOM7h-11-18: 98.2%, DOM7h-11-19: 97.2%)
[0125] The minimum identity to parent (at the amino acid level) of the clones selected was 96.3% (DOM7h-14-10: 96.3%, DOM7h-14-18: 96.3%, DOM7h-14-19: 98.2%, DOM7h-14-28: 99.1%, DOM7h-14-36: 97.2%)
[0126] Unique dAbs were expressed as bacterial supernatants in 2.5 L shake flasks in Onex media at 30° C. for 48 hrs at 250 rpm. dAbs were purified from the culture media by absorption to protein L agarose followed by elution with 10 mM glycine pH2.0. Binding to HSA, CSA, MSA and RSA by BIAcore was confirmed using purified protein at 3 concentrations 1 μM, 500 nM and 50 nM. To determine the binding affinity (KD) of the AlbudAbs to each serum albumin; purified dAbs were analysed by BIAcore over albumin concentration range from 5000 nM to 39 nM (5000 nM, 2500 nM, 1250 nM, 625 nM, 312 nM, 156 nM, 78 nM, 39 nM).
TABLE-US-00008 TABLE 6 Affinity (KD) AlbudAb to SA (nM) Kd Ka Rat DOM7h-14 60 2.095E-01 4.00E+06 DOM7h-14-10 4 9.640E-03 4.57E+06 DOM7h-14-18 410 2.275E-01 5.60E+05 DOM 7h-14-19 890 2.870E-01 3.20E+05 DOM 7h-14-28 45 (140) 7.0E-02 (1.141e-1) 2.10E+06 (8.3e5) DOM 7h-14-36 30 (6120) 2.9E-02 (5.54e-2) 1.55E+06 (9e3) DOM 7h-11 2100 1.00E-01 4.80E+04 DOM 7h-11-3 10000 (88000) (7.18e-1) (8.11e3) DOM 7h-11-12 200 5.22E-01 2.76E+06 DOM 7h-11-15 20 2.10E-02 1.10E+06 DOM 7h-11-18 80 (29000) 6.0E-02 (3.7e-1) 1.64E+06 (1.3e4) DOM 7h-11-19 28 (17000) 9.1e-02 (1.4e-1) 9.80E+05 (8.1e3) Cyno DOM 7h-14 66 9.65E-02 1.50E+06 DOM 7h-14-10 9 1.15E-02 1.60E+06 DOM 7h-14-18 180 1.05E-01 6.30E+5 DOM 7h-14-19 225 1.56E-01 7.00E+05 DOM 7h-14-28 66 (136) 1.3E-01 (1.34e-1) 2.50E+06 (9.8e5) DOM 7h-14-36 35 (7830) 1.9E-02 (1.1e-1) 9.80E+06 (1.43e4) DOM 7h-11 1000 6.82E-01 8.00E+05 DOM 7h-11-3 670 (200) 9.6E-02 (1.5e-1) 2.90E+05 (7.26e5) DOM 7h-11-12 ≧6000 DOM 7h-11-15 3 5.57E-03 5.80E+06 DOM 7h-11-18 10000 (65000) 1.36 (4.8e-1) 2.25E+05 (7.3e3) DOM 7h-11-19 ≧10000 (375000) (6.2e-1) (1.7e3) Mouse DOM 7h-14 12 4.82E-02 4.10E+06 DOM 7h-14-10 30 3.41E-02 1.29E+06 DOM 7h-14-18 65 9.24E-02 2.28E+06 DOM 7h-14-19 60 5.76E-02 1.16E+06 DOM 7h-14-28 26 (31) 3.4E-02 (7.15e-2) 1.60E+06 (2.28e6) DOM 7h-14-36 35 (33) 2.3E-02 (7.06e-2) 8.70E+05 (2.11e6) DOM 7h-11 5000 9.00E-01 DOM 7h-11-3 ≧10000 (36000) (6.12e-1) (1.67e4) DOM 7h-11-12 130 1.89E-01 1.53E+06 DOM 7h-11-15 10 9.40E-03 1.10E+06 DOM 7h-11-18 150 (1600) 2.4E-02 (6.23e-2) 4.40E+05 (4e4) DOM 7h-11-19 100 (18000) 3.7E-02 (8.8e-2) 1.40E+06 (4.9e3) Human DOM 7h-14 33 4.17E-02 1.43E+06 DOM 7h-14-10 12 1.39E-02 1.50E+06 DOM 7h-14-18 280 3.39E-02 1.89E+05 DOM 7h-14-19 70 5.25E-02 8.26E+05 DOM 7h-14-28 30 (8260) 3.3E-02 (5.6e-2) 1.24E+06 (6.78e3) DOM 7h-14-36 28 (1260) 2.4E-02 (6.7e-2) 1.23E+06 (5.4e4) DOM 7h-11 2800 6.41E-01 7.00E+05 DOM 7h-11-3 32 (130) 1.6E-02 (2.35e-2) 6.50E+05 (1.86e5) DOM 7h-11-12 350 4.13E-01 1.26E+06 DOM 7h-11-15 1 1.84E-03 2.00E+06 DOM 7h-11-18 36 (32000) 5.1E-02 (2.7e-1) 3.40E+06 (8.39e3) DOM 7h-11-19 65 (38000) 1.1E-01 (2.09e-1) 1.80E+06 (5.4e3) * values in brackets were derived from a second, independent SPR experiment.
[0127] All DOM7h-14 derived variants are cross-reactive to mouse, rat, human and cyno serum albumin. DOM7h-14-10 has improved affinity to rat, cyno and human serum albumin compared to parent. DOM7h-14-28 has an improved affinity to RSA. DOM7h-14-36 has an improved affinity to RSA, CSA and MSA.
[0128] DOM7h-11-3 has improved affinity to CSA and HSA. DOM7h-11-12 has improved affinity to RSA, MSA and HSA. DOM7h-11-15 has improved affinity to RSA, MSA, CSA and HSA. DOM7h-11-18 and DOM7h-11-19 have improved affinity to RSA, MSA and HSA.
Example 3
Origins of Key DOM7h-11 Lineage Clones
[0129] DOM7h-11-3: From affinity maturation performed against HSA using the CDR2 library (Y49, A50, A51, S53), round 3 output 10 nM HSA.
[0130] DOM7h-11-12: From affinity maturation performed against HSA using the error prone library, round 3 outputs (100 nM, HSA) with 100 ug/ml trypsin.
[0131] DOM7h-11-15: From cross-over selections performed against HSA as round 1 followed by additional 3 rounds of selections against RSA using the CDR2 library (Y49, A50, A51, S53) at round 3 selection with 1 nM of RSA.
[0132] DOM7h-11-18 From cross-over selections performed against HSA as round 1 followed by additional 3 rounds of selections against RSA using the error prone library, round 3 output at 20 nM of RSA
[0133] DOM7h-11-19 From cross-over selections performed against HSA as round 1 followed by additional 3 rounds of selections against RSA using the error prone library, round 3 output at 5 nM of RSA
TABLE-US-00009 TABLE 7 CDR sequences (according to Kabat; ref. as above) CDR AlbudAb CDR1 CDR2 CDR3 DPK9 Vk SQSISSYLN YAASSLQS QQSYSTPNT dummy (SEQ ID (SEQ ID (SEQ ID NO: 337) NO: 338) NO: 339) DOM SRPIGTTLS WFGSRLQS AQAGTHPTT 7h-11 (SEQ ID (SEQ ID (SEQ ID NO: 340) NO: 341) NO: 342) DOM SRPIGTMLS LFGSRLQS AQAGTHPTT 7h-11-12 (SEQ ID (SEQ ID (SEQ ID NO: 343) NO: 344) NO: 345) DOM SRPIGTMLS LAFSRLQS AQAGTHPTT 7h-11-15 (SEQ ID (SEQ ID (SEQ ID NO: 346) NO: 347) NO: 348) DOM SRPIGTMLS WFGSRLQS AQAGTHPTT 7h-11-18 (SEQ ID (SEQ ID (SEQ ID NO: 349) NO: 350) NO: 351) DOM SRPIGTMLS LFGSRLQS AQTGTHPTT 7h-11-19 (SEQ ID (SEQ ID (SEQ ID NO: 352) NO: 353) NO: 354) DOM SRPIGTTLS LWFSRLQS AQAGTHPTT 7h-11-3 (SEQ ID (SEQ ID (SEQ ID NO: 355) NO: 356) NO: 357)
Example 4
Origins of Key DOM7h-14 Lineage Clones
[0134] DOM7h-14-19: From affinity maturation performed against HSA using the error prone library, round 3 outputs (100 nM, HSA) with 100 ug/ml trypsin.
[0135] DOM7h-14-10, DOM7h-14-18, DOM7h-14-28, DOM7h-14-36: From affinity maturation performed against HSA using CDR3 library (Y92, Y93, T94, N96), round 3 output.
TABLE-US-00010 TABLE 8 CDR sequences (according to Kabat; ref. as above) CDR AlbudAb CDR1 CDR2 CDR3 DPK9 Vk SQSISSYLN YAASSLQS QQSYSTPNT dummy (SEQ ID (SEQ ID (SEQ ID NO: 337) NO: 338) NO: 339) DOM SQWIGSQLS MWRSSLQS AQGAALPRT 7h-14 (SEQ ID (SEQ ID (SEQ ID NO: 358) NO: 359) NO: 360) DOM SQWIGSQLS MWRSSLQS AQGLRHPKT 7h-14-10 (SEQ ID (SEQ ID (SEQ ID NO: 361) NO: 362) NO: 363) DOM SQWIGSQLS MWRSSLQS AQGLMKPMT 7h-14-18 (SEQ ID (SEQ ID (SEQ ID NO: 364) NO: 365) NO: 366) DOM SQWIGSQLS MWRSSLQS AQGAALPRT 7h-14-19 (SEQ ID (SEQ ID (SEQ ID NO: 367) NO: 368) NO: 369) DOM SQWIGSQLS MWRSSLQS AQGAALPKT 7h-14-28 (SEQ ID (SEQ ID (SEQ ID NO: 370) NO: 371) NO: 372) DOM SQWIGSQLS MWRSSLQS AQGFKKPRT 7h-14-36 (SEQ ID (SEQ ID (SEQ ID NO: 373) NO: 374) NO: 375)
Example 5
Expression and Biophysical Characterisation
[0136] The routine bacterial expression level in 2.5 L shake flasks was determined following culture in Onex media at 30° C. for 48 hrs at 250 rpm. The biophysical characteristics were determined by SEC MALLS and DSC.
[0137] SEC MALLS (size exclusion chromatography with multi-angle-LASER-light-scattering) is a non-invasive technique for the characterizing of macromolecules in solution. Briefly, proteins (at concentration of 1 mg/mL in buffer Dulbecco's PBS at 0.5 ml/min are separated according to their hydrodynamic properties by size exclusion chromatography (column: TSK3000 from TOSOH Biosciences; 5200 from Pharmacia). Following separation, the propensity of the protein to scatter light is measured using a multi-angle-LASER-light-scattering (MALLS) detector. The intensity of the scattered light while protein passes through the detector is measured as a function of angle. This measurement taken together with the protein concentration determined using the refractive index (RI) detector allows calculation of the molar mass using appropriate equations (integral part of the analysis software Astra v.5.3.4.12).
[0138] DSC (Differential Scanning calorimetry): briefly, the protein is heated at a constant rate of 180° C./hrs (at 1 mg/mL in PBS) and a detectable heat change associated with thermal denaturation measured. The transition midpoint (appTm) is determined, which is described as the temperature where 50% of the protein is in its native conformation and the other 50% is denatured. Here, DSC determined the apparent transition midpoint (appTm) as most of the proteins examined do not fully refold. The higher the Tm, the more stable the molecule. Unfolding curves were analysed by non-2-state equations. The software package used was Origin' v7.0383.
TABLE-US-00011 TABLE 9 Biophysical parameters AlbudAb SEC MALLS DSC Tm(° C.) DOM7h-14 M 60 DOM 7h-14-10 M 59 DOM 7h-14-18 M 58 DOM 7h-14-19 M 59 DOM 7h-14-28 M 58.3/60.2 DOM 7h-14-36 M 59.2 DOM 7h-11 M 66.9-72.2 DOM 7h-11-3 M (95%)* 66.6/70.5 DOM 7h-11-12 M (<2% D) 71.7 DOM 7h-11-15 M (<5% D) 58.5-60.5 DOM 7h-11-18 M (98%) 58.9/65.8 DOM 7h-11-19 M 71.8/76.6 *in one other trial, monomer was primarily seen by SEC MALLS, although lower than 95%
[0139] Expression levels for all clones in Table 9 were observed in the range from 15 to 119 mg/L in E coli.
[0140] For DOM7h-14 and DOM7h-11 variants, favorable biophysical parameters (monomeric in solution as determined by SEC MALLs and appTm of >55° C. as determined by DSC) and expression levels were maintained during affinity maturation. Monomeric state is advantageous because it avoids dimerisation and the risk of products that may cross-link targets such as cell-surface receptors.
Example 6
Determination of Serum Half Life in Rat, Mouse and Cynomolgus Monkey
[0141] AlbudAbs DOM7h-14-10, DOM7h-14-18, DOM7h-14-19, DOM7h-11, DOM7h11-12 and DOM7h-11-15 were cloned into the pDOM5 vector. For each AlbudAb®, 20-50 mg quantities were expressed in E. coli and purified from bacterial culture supernatant using protein L affinity resin and eluted with 100 mM glycine pH2. The proteins were concentrated to greater than 1 mg/ml, buffer exchanged into PBS and endotoxin depleted using Q spin columns (Vivascience). For Rat pharmacokinetic (PK) analysis, AlbudAbs were dosed as single i.v injections at 2.5 mg/kg using 3 rats per compound. Serum samples were taken at 0.16, 1, 4, 12, 24, 48, 72, 120, 168 hrs. Analysis of serum levels was by anti-myc ELISA as per the method described below.
[0142] For Mouse PK, DOM7h-11, DOM7h11-12 and DOM7h-11-15 were dosed as single i.v injections at 2.5 mg/kg per dose group of 3 subjects and serum samples taken at 10 mins; 1h; 8h; 24h; 48h; 72h; 96h. Analysis of serum levels was by anti-myc ELISA as per the method described below.
[0143] For Cynomolgus monkey PK DOM7h-14-10 and DOM7h-11-15 were dosed as single i.v injections at 2.5 mg/kg into 3 female Cynomolgus monkeys per dose group and serum samples taken at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 192, 288, 336, 504 hrs. Analysis of serum levels was by anti-myc ELISA as per the method described below.
Anti-Myc ELISA Method
[0144] The AlbudAb concentration in serum was measured by anti-myc ELISA. Briefly, goat anti-myc polyclonal antibody (1:500; Abcam, catalogue number ab9132) was coated overnight onto Nunc 96-well Maxisorp plates and blocked with 5% BSA/PBS+1% tween. Serum samples were added at a range of dilutions alongside a standard at known concentrations. Bound myc-tagged AlbudAb was then detected using a rabbit polyclonal anti-Vk (1:1000; in-house reagent, bleeds were pooled and protein A purified before use) followed by an anti-rabbit IgG HRP antibody (1:10,000; Sigma, catalogue number A2074). Plates were washed between each stage of the assay with 3×PBS+0.1% Tween20 followed by 3×PBS. TMB (SureBlue TMB 1-Component Microwell Peroxidase Substrate, KPL, catalogue number 52-00-00) was added after the last wash and was allowed to develop. This was stopped with 1M HCl and the signal was then measured using absorbance at 450 nm.
[0145] From the raw ELISA data, the concentration of unknown samples was established by interpolation against the standard curve taking into account dilution factors. The mean concentration result from each time point was determined from replicate values and entered into WinNonLin analysis package (eg version 5.1 (available from Pharsight Corp., Mountain View, Calif. 94040, USA). The data was fitted using a non-compartmental model, where PK parameters were estimated by the software to give terminal half-lives. Dosing information and time points were selected to reflect the terminal phase of each PK profile.
TABLE-US-00012 TABLE 10 Single AlbudAb ® PK PK parameters AUC CL Spe- Albumin h × ml/h/ t1/2 Vz cies AlbudAb KD (nM) μg/ml kg h ml/kg Rat DOM7h-14* 60 DOM7h-14-10 4 2134.6 1.2 42.1 71.2 DOM7h-14-18 410 617.3 4.1 38.4 228.1 DOM 7h-14-19 890 632.6 4.1 36.3 213.3 DOM 7h-11 2100 320.1 7.8 23.3 263.9 DOM 7h-11-12 200 398.7 6.4 35.5 321.2 DOM 7h-11-15 20 843.4 3.0 30.3 130.7 mouse DOM 7h-11 5000 304.7 8.2 18.3 216.8 DOM 7h-11-12 130 646.6 3.9 43.9 244.8 DOM 7h-11-15 10 499.2 5.0 33.7 243.4 Cyno DOM 7h-14* 66 217.5 DOM 7h-14-10 9 6174.6 0.4 200.8 117.8 DOM 7h-11* 3300 135.1 DOM 7h-11-15 3 4195 0.6 198.1 170.3 *Historical data Pharmacokinetic parameters derived from rat, mouse and cynomolgus monkey studies were fitted using a non-compartmental model. Key: AUC: Area under the curve from dosing time extrapolated to infinity; CL: clearance; t1/2: is the time during which the blood concentration is halved; Vz: volume of distribution based on the terminal phase.
[0146] DOM7h-11 12 and DOM7h-11-15 have an improved AUC and t1/2 in rat and mouse compared to parent. DOM7h-11-15 also has an improved AUC and t1/2 in cyno compared to parent. This improvement in AUC/t1/2 correlates with an improved in vitro KD to serum albumin.
Example 7
AlbudAb® IFN Fusions
Cloning and Expression
[0147] As well as single AlbudAbs, the affinity matured Vk AlbudAbs were linked to Interferon alpha 2b (IFNα2b) to determine whether a useful PK of the AlbudAb was maintained as a fusion protein.
Interferon Alpha 2b Amino Acid Sequence:
TABLE-US-00013
[0148] (SEQ ID NO: 376) CDLPQTHSLGSRRTLMLLAQMRRISLFSCLKDRHDFGFPQEEFGNQFQK AETIPVLHEMIQQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEAC VIQGVGVTETPLMKEDSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEI MRSFSLSTNLQESLRSKE
Interferon Alpha 2b Nucleotide Sequence:
TABLE-US-00014
[0149] (SEQ ID NO: 377) TGTGATCTGCCTCAAACCCACAGCCTGGGTAGCAGGAGGACCTTGATGC TCCTGGCACAGATGAGGAGAATCTCTCTTTTCTCCTGCTTGAAGGACAG ACATGACTTTGGATTTCCCCAGGAGGAGTTTGGCAACCAGTTCCAAAAG GCTGAAACCATCCCTGTCCTCCATGAGATGATCCAGCAGATCTTCAATC TCTTCAGCACAAAGGACTCATCTGCTGCTTGGGATGAGACCCTCCTAGA CAAATTCTACACTGAACTCTACCAGCAGCTGAATGACCTGGAAGCCTGT GTGATACAGGGGGTGGGGGTGACAGAGACTCCCCTGATGAAGGAGGACT CCATTCTGGCTGTGAGGAAATACTTCCAAAGAATCACTCTCTATCTGAA AGAGAAGAAATACAGCCCTTGTGCCTGGGAGGTTGTCAGAGCAGAAATC ATGAGATCTTTTTCTTTGTCAACAAACTTGCAAGAAAGTTTAAGAAGTA AGGAA
[0150] IFNa2b was linked to the AlbudAb via a TVAAPS linker region (see WO2007085814). The constructs were cloned by SOE-PCR (single overlap extension according to the method of Horton et al. Gene, 77, p 61 (1989)). PCR amplification of the AlbudAb and IFN sequences were carried out separately using primers with a ˜15 base pair overlap at the TVAAPS linker region. The primers used are as follows:--
TABLE-US-00015 IFNα2b SOE fragment 5' (SEQ ID NO: 378) GCCCGGATCCACCGGCTGTGATCTG IFNα2b SOE fragment 3' (SEQ ID NO: 379) GGAGGATGGAGACTGGGTCATCTGGATGTC Vk SOE fragment 5' (SEQ ID NO: 380) GACATCCAGATGACCCAGTCTCCATCCTCC Vk SOE fragment 3' to also introduce a myc tag (SEQ ID NO: 381) GCGCAAGCTTTTATTAATTCAGATCCTCTTCTGAGATGAGTTTTTG TTCTGCGGCCGCCCGTTTGATTTCCACCTTGGTCCC
[0151] The fragments were purified separately and subsequently assembled in a SOE (single overlap extension PCR extension) reaction using only the flanking primers.
TABLE-US-00016 IFNα2b SOE fragment 5' (SEQ ID NO: 382) GCCCGGATCCACCGGCTGTGATCTGGCGCAAGCTTTTATTAATTCA GATCCTCTTC Vk SOE fragment 3' to also introduce a myc tag (SEQ ID NO: 383) TGAGATGAGTTTTTGTTCTGCGGCCGCCCGTTTGATTTCCACCTTG GTCCC
[0152] The assembled PCR product was digested using the restriction enzymes BamHI and HindIII and the gene ligated into the corresponding sites in the pDOM50, a mammalian expression vector which is a pTT5 derivative with an N-terminal V-J2-C mouse IgG secretory leader sequence to facilitate expression into the cell media.
Leader Sequence (Amino Acid):
TABLE-US-00017
[0153] (SEQ ID NO: 384) METDTLLLWVLLLWVPGSTG
Leader Sequence (Nucleotide):
TABLE-US-00018
[0154] (SEQ ID NO: 385) ATGGAGACCGACACCCTGCTGCTGTGGGTGCTGCTGCTGTGGGTGC CCGGATCCACCGGGC
[0155] Plasmid DNA was prepared using QIAfilter megaprep (Qiagen). 1 μg DNA/ml was transfected with 293-Fectin into HEK293E cells and grown in serum free media. The protein is expressed in culture for 5 days and purified from culture supernatant using protein L affinity resin and eluted with 100 mM glycine pH2. The proteins were concentrated to greater than 1 mg/ml, buffer exchanged into PBS and endotoxin depleted using Q spin columns (Vivascience).
Affinity Determination and Biophysical Characterisation:
[0156] To determine the binding affinity (KD) of the AlbudAb-IFNα2b fusion proteins to each serum albumin; purified fusion proteins were analysed by BIAcore over albumin (immobilised by primary-amine coupling onto CM5 chips; BIAcore) using fusion protein concentrations from 5000 nM to 39 nM (5000 nM, 2500 nM, 1250 nM, 625 nM, 312 nM, 156 nM, 78 nM, 39 nM) in HBS-EP BIAcore buffer.
TABLE-US-00019 TABLE 12 Affinity to SA Affinity to AlbudAb Fusion SA (nM) Kd Ka Rat DOM7h-14 IFNα2b 350 4.500E-02 1.28E+05 DOM7h-14-10 IFNα2b 16 4.970E-03 5.90E+05 DOM 7h-14-18 IFNα2b 780 2.127E-01 5.80E+05 DOM 7h-14-19 IFNα2b 1900 1.206E-01 7.96E+04 DOM 7h-11 IFNα2b 6000 7.500E-01 nd DOM 7h-11-12 IFNα2b 1700 3.100E-01 1.30E+05 DOM 7h-11-15 IFNα2b 200 1.660E-02 1.50E+05 Cyno DOM 7h-14 IFNα2b 60 1.32E-02 5.0E+05 DOM 7h-14-10 IFNα2b 19 7.05E-03 4.50E+05 DOM 7h-14-18 IFNα2b no binding no binding no binding DOM 7h-14-19 IFNα2b 520 8.47E-02 2.73E+05 DOM 7h-11 IFNα2b 3300 3.59E-01 1.20E+05 DOM 7h-11-12 IFNα2b 630 3.45E-01 7.00E+05 DOM 7h-11-15 IFNα2b 15 4.86E-03 3.60E+05 Mouse DOM 7h-14 IFNα2b 240 3.21E-02 1.50E+06 DOM 7h-14-10 IFNα2b 60 3.45E-02 6.86E+05 DOM 7h-14-18 IFNα2b 180 1.50E-01 9.84E+05 DOM 7h-14-19 IFNα2b 490 4.03E-02 1.19E+05 DOM 7h-11 IFNα2b 6000 1.55E-01 nd DOM 7h-11-12 IFNα2b 150 9.49E-02 6.30E+05 DOM 7h-11-15 IFNα2b 28 6.69E-03 2.80E+05 Human DOM 7h-14 IFNα2b 244 2.21E-02 9.89E+04 DOM 7h-14-10 IFNα2b 32 6.58E-03 3.48E+05 DOM 7h-14-18 IFNα2b 470 2.75E-01 6.15E+05 DOM 7h-14-19 IFNα2b 350 4.19E-02 1.55E+05 DOM 7h-11 IFNα2b 670 2.02E-01 7.00E+05 DOM 7h-11-12 IFNα2b 500 1.66E-01 3.90E+05 DOM 7h-11-15 IFNα2b 10 1.87E-03 3.50E+05
[0157] When IFNα2b is linked to the AlbudAb variants, in all cases the affinity of AlbudAb binding to serum albumin is reduced. DOM7h-14-10 and DOM7-11-15 retain improved binding affinity to serum albumin across species compared to parent. DOM7h-11-12 also shows improved binding affinity to serum albumin across species compared to parent.
TABLE-US-00020 TABLE 13 Biophysical Characterisation Biophysical Characterisation was carried out by SEC MALLS and DSC as described above for the single AlbudAbs. DMS Biophysical parameters AlbudAb Fusion number SEC MALLS DSC Tm(° C.) DOM 7h-14 IFNα2b DMS7321 M/D 58-65 DOM 7h-14-10 IFNα2b DMS7322 M/D 55-65 DOM 7h-14-18 IFNα2b DMS7323 M/D 55-65 DOM 7h-14-19 IFNα2b DMS7324 M/D 59-66 DOM 7h-11 IFNα2b DMS7325 M/D 65.8-66.2 DOM 7h-11-12 IFNα2b DMS7326 M/D .sup. 67-67.3 DOM 7h-11-15 IFNα2b DMS7327 M/D 56.3-66.2
[0158] M/D indicates a monomer/dimer equilibrium as detected by SEC MALLS
[0159] Expression for all clones in Table 13 was observed in the range of 17.5 to 54 mg/L in HEK293.
[0160] For IFNα2b-DOM7h-14 and IFNα2b-DOM7h-11 variants, favorable biophysical parameters and expression levels were maintained during affinity maturation.
PK Determination for AlbudAb-IFNα2bfusions
[0161] AlbudAbs IFNα2b fusions DMS7321 (IFNα2b-DOM7h-14) DMS7322 (IFNα2b-DOM7h-14-10) DMS7323 (IFNα2b-DOM7h-14-18), DMS7324 (IFNα2b-DOM7h-14-19), DMS7325 (IFNα2b-DOM7h-11), DMS7326 (IFNα2b-DOM7h-11-12), DMS7327 (IFNα2b-DOM7h-11-15) were expressed with the myc tag at 20-50 mg quantities in HEK293 cells and purified from culture supernatant using protein L affinity resin and eluted with 100 mM glycine pH2. The proteins were concentrated to greater than 1 mg/ml, buffer exchanged into Dulbecco's PBS and endotoxin depleted using Q spin columns (Vivascience).
[0162] For Rat PK, IFN-AlbudAbs were dosed as single i.v injections at 2.0 mg/kg using 3 rats per compound. Serum samples were taken at 0.16, 1, 4, 8, 24, 48, 72, 120, 168 hrs. Analysis of serum levels was by EASY ELISA according to manufacturer's instructions (GE Healthcare, catalogue number RPN5960).
[0163] For Mouse PK, DMS7322 (IFN2b-DOM7h-14-10) DMS7325 (IFN2b-DOM7h-11), DMS7326 (IFN2b-DOM7h-11-12), DMS7327 (IFN2b-DOM7h-11-15) all with myc tags were dosed as single i.v injections at 2.0 mg/kg per dose group of 3 subjects and serum samples taken at 10 mins; 1h; 8h; 24h; 48h; 72h; 96h. Analysis of serum levels was by EASY ELISA according to manufacturer's instructions (GE Healthcare, catalogue number RPN5960).
TABLE-US-00021 TABLE 14 PK parameters AUC CL Spe- Albumin h × ml/h/ t1/2 Vz cies AlbudAb Fusion KD (nM) ug/ml kg h ml/kg Rat 7h-14 IFNα2b 350 832.1 2.4 27 94.5 7h-14-10 IFNα2b 16 1380.7 1.5 35.8 75.2 7h-14-18 IFNα2b 780 691.2 2.9 22.4 93.7 7h-14-19 IFNα2b 1900 969.4 2.2 25 78.7 7h-11 IFNα2b 6000 327.9 6.5 11 101.9 7h-11-12 IFNα2b 1700 747.1 2.8 25.8 104.7 7h-11-15 IFNα2b 200 1118.7 1.8 39.5 103.6 Mouse 7h-14 IFNα2b 240 761.2 2.6 30.4 115.3 7h-14-10 IFNα2b 60 750.5 2.7 30.9 118.6 7h-11 IFNα2b 6000 493.9 4.0 8.8 51.2 7h-11-12 IFNα2b 150 439.6 4.5 21.5 140.9 7h-11-15 IFNα2b 28 971.8 2.1 33.6 99.6 Pharmacokinetic parameters derived from rat and mouse studies were fitted using a non-compartmental model. Key: AUC: Area under the curve from dosing time extrapolated to infinity; CL: clearance; t1/2: is the time during which the blood concentration is halved; Vz: volume of distribution based on the terminal phase.
[0164] IFNα2b-AlbudAbs were tested in rat and mouse. For all IFNα2b-DOM7h-11 variant fusion proteins in both rat and mouse, t1/2 is improved compared to parent. The improvement in t1/2 correlates with the improved in vitro KD to serum albumin. For IFNα2b-DOM7h-14-10 variants, the improvement in in vitro KD to serum albumin also correlated to an improvement in t1/2 in rat.
[0165] All IFNα2b-AlbudAb fusion proteins exhibit a 5 to 10-fold decrease in the binding to RSA compared to the single AlbudAb. This effect is more pronounced (i.e. 10-fold) for the DOM7h-14 series than the DOM7h-11 series (only 5-fold decrease).
Example 8
Further AlbudAb Fusions with Proteins, Peptides and NCEs
[0166] Various AlbudAbs fused to other chemical entities namely domain antibodies (dAbs), peptides and NCEs were tested. The results are shown in table 15.
TABLE-US-00022 TABLE 15 PK parameters AUC CL Spe- Albumin h × ml/h/ t1/2 Vz cies AlbudAb Fusion KD (nM) ug/ml kg h ml/kg Rat DOM7h-14 Exendin-4 2400 18 57.1 11 901.9 DOM7h-14-10 Exendin-4 19 43.6 23.1 22.1 740.3 DOM7h-14-18 Exendin-4 16000 16.9 75.7 9.4 1002.5 DOM7h-14-19 Exendin-4 17000 31.4 32.5 11.9 556.7 DOM7h-11 Exendin-4 24000 6.1 168 7.1 1684.1 DOM7h-11-12 Exendin-4 1400 24.2 59.9 13 1068.7 DOM7h-11-15 Exendin-4 130 36.3 27.6 19.3 765.7 DOM7h14-10 NCE-GGGGSC 62 DOM7h14-10 NCE-TVAAPSC 35 Human DOM7h-14 NCE 204 Mouse DOM7h-11 DOM1m-21-23 234 10.7 4.7 72.5 DOM7h-11-12 DOM1m-21-23 755 3.3 18 86.2 DOM7h-11-15 DOM1m-21-23 1008 2.5 17.4 62.4 Key: DOM1m-21-23 is an anti-TNFR1 dAb, Exendin-4 is a peptide (a GLP-1 agonist) of 39 amino acids length. NCE, NCE-GGGGSC and NCE-TVAAPSC are described below.
[0167] Previously, the use of genetic fusions with an albumin-binding dAb (AlbudAb) to extend the PK half-life of anti-TNFR1 dAbs in vivo was described (see, eg, WO04003019, WO2006038027, WO2008149148). Reference is made to the protocols in these PCT applications. In the table above, DOM1m-21-23 is an anti-mouse TNFR1 dAb.
[0168] To produce genetic fusions of exendin-4 or with DOM7h-14 (or other AlbudAb) which binds serum albumin, the exendin-4-linker-AlbudAb sequence was cloned into the pTT-5 vector (obtainable from CNRC, Canada). In each case the exendin-4 was at the 5' end of the construct and the dAb at the 3' end. The linker was a (G4S)3 linker. Endotoxin-free DNA was prepared in E. coli using alkaline lysis (using the endotoxin-free plasmid Giga kit, obtainable from Qiagen CA) and used to transfect HEK293E cells (obtainable from CNRC, Canada). Transfection was into 250 ml/flask of HEK293E cells at 1.75×106 cells/ml using 333 ul of 293fectin (Invitrogen) and 250 ug of DNA per flask and expression was at 30° C. for 5 days. The supernatant was harvested by centrifugation and purification was by affinity purification on protein L. Protein was batch bound to the resin, packed on a column and washed with 10 column volumes of PBS. Protein was eluted with 50 ml of 0.1M glycine pH2 and neutralised with Tris pH8. Protein of the expected size was identified on an SDS-PAGE gel.
NCE Albudab Fusions:
[0169] A new chemical entity (NCE) AlbudAb fusion was tested. The NCE, a small molecule ADAMTS-4 inhibitor was synthesised with a PEG linker (PEG 4 linker (ie 4 PEG molecules before the maleimide) and a maleimide group for conjugation to the AlbudAb. Conjugation of the NCE to the AlbudAb is via an engineered cystine residue at amino acid position R108C, or following a 5 amino acid (GGGGSC) or 6 amino acid (TVAAPSC) spacer engineered at the end of the AlbudAb. Briefly, the AlbudAb was reduced with TCEP (Pierce, Catalogue Number 77720), desalted using a PD10 column (GE healthcare) into 25 mM Bis-Tris, 5 mM EDTA, 10% (v/v) glycerol pH6.5. A 5 fold molar excess of maleimide activated NCE was added in DMSO not to exceed 10% (V/V) final concentration. The reaction was incubated over night at room temperature and dialysed extensively into 20 mM Tris pH7.4
PEG Linker:
##STR00001##
[0170] Sequences:
TABLE-US-00023
[0171] DOM7h-14 R108C: (SEQ ID NO: 386) DIQMTQSPSSLSASVGDRVTITCRASQWIGSQLSWYQQKPGKAPKLLI MWRSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQGLRHPK TFGQGTKVEIKC Nucleotide: (SEQ ID NO: 387) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA GACCGTGTCACCATCACTTGCCGGGCAAGTCAGTGGATTGGGTCTCAG TTATCTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATC ATGTGGCGTTCCTCGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGC AGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCT GAAGATTTTGCTACGTACTACTGTGCTCAGGGTTTGAGGCATCCTAAG ACGTTCGGCCAAGGGACCAAGGTGGAAATCAAATGC
[0172] See Table 5 for the sequences of DOM7h-14-10/TVAAPSC and DOM7h-14-10/GGGGSC (ie, DOM7h-14-10/G4SC).
[0173] NCE-AlbudAbs DOM7h-14-10 GGGGSC and DOM7h14-10 TVAAPSC, exhibit a 5 to 10 fold decrease in in vitro affinity (KD) to RSA as determined by BIAcore when fused to the chemical entity. PK data are not available for these molecules yet.
[0174] dAb-Albudab fusion: the 2 DOM7h-11 AlbudAbs with the highest affinity to RSA experience a 2-fold decrease in affinity to RSA as on BIAcore when fused to a therapeutic domain antibody (DOM1m-21-23) compared to the unfused AlbudAb. The DOM7h-11 clone shows a micromolar KD when fused (2.8 uM) as well as when unfused (˜5 uM).
[0175] Exendin 4-AlbudAb fusion: the effect of fusing the AlbudAbs to a peptide on the binding ability to RSA is about 10-fold, apart from DOM7h-14-10, which only shows a 4-fold decrease in binding. The effect, however, is more pronounced for the DOM7h-14 series (except DOM7h-14-10) than it appears to be for the DOM7h-11 series.
[0176] For all the above data, the T1/2 of the fusion increased with improved affinity to the species' SA.
[0177] Generally, Albudab-therapeutics are classified as being therapeutically amenable (for treatment and/or prophylaxis of diseases, conditions or indications) when the AlbudAb-drug fusions show an affinity range (KD) of from 0.1 nM to 10 mM for serum albumin binding.
[0178] The therapeutic ranges of AlbudAbs and AlbudAb fusions (Protein-AlbudAbs for example IFNa2b-DOM7h-14-10; Peptide-AlbudAbs for example Exendin-4-DOM7h-14-10; dAb-AlbudAbs for example DOM1m21-23-DOM7h11-15; NCE-AlbudAb for example ADAMTS-4-DOM7h-14-10) are described as follows: Affinity (KD) ranges that are useful for therapy of chronic or acute conditions, diseases or indications are shown. Also shown are affinity ranges marked as "intermediate". AlbudAbs and fusions in this range have utility for chronic or acute diseases, conditions or indications. In this way, the affinity of the AlbudAb or fusion for serum albumin can be tailored or chosen according to the disease, condition or indication to be addressed. As described above, the invention provides AlbudAbs with affinities that allow for each AlbudAb to be categorised as "high affinity", "medium affinity" or "low affinity", thus enabling the skilled person to select the appropriate AlbudAb of the invention according to the therapy at hand. See FIG. 2.
Example 9
DOM7h-11-15.sup.S12P Sequences
[0179] Amino Acid Sequence of DOM7h-11-15.sup.S12P
TABLE-US-00024 (SEQ ID NO: 388) DIQMTQSPSSLPASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLLI LAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPT TFGQGTKVEIKR
[0180] An aspect of the invention provides a nucleic acid comprising the nucleotide sequence of DOM7h-11-15.sup.S12P or a nucleotide sequence that is at least 80% identical to said selected sequence. DOM7h-11-15.sup.S12P was produced using the following nucleic acid sequence (the underlined C denotes the change (versus the nucleic acid encoding DOM7h-11-15) leading to a proline at position 12):--
TABLE-US-00025 (SEQ ID NO: 389) GACATCCAGATGACCCAGTCTCCATCCTCCCTGCCTGCATCTGTAGGA GACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATG TTAAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATC CTTGCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGC AGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCT GAAGATTTTGCTACGTACTACTGCGCGCAGGCTGGGACGCATCCTACG ACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGG
DOM7h-11-15.sup.S12P was constructed by using DOM7h-11-15 as a template in a PCR where a primer was used to introduce the 512P mutation. The primer sequence is:--
TABLE-US-00026 (SEQ ID NO: 390) GCAACAGCGTCGACGGACATCCAGATGACCCAGTCTCCATCCTCCCTG CCTGCATCTGTAGG.
[0181] An alternative aspect of the invention provides a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 389 or a nucleotide sequence that is at least 80% identical to said selected sequence. In one embodiment, DOM7h-11-15.sup.S12P is encoded by, and expressed from, a vector that contains a linker region and a C-terminal sequence encoding a protein or peptide drug or a single variable domain or other antibody fragment to make the in-line protein fusion product. The linker, in one embodiment, comprises the amino acid sequence TVA, e.g., TVAAPS. Other aspects of the invention are a vector comprising the nucleic acid; and an isolated host cell comprising the vector. The invention also provides a method of treating or preventing a disease or disorder in a patient, comprising administering at least one dose of DOM7h-11-15.sup.S12P to said patient.
Example 10
DOM 7h-11-15 Variants
[0182] i) Vk Affinity Maturation
Selections:
[0183] HSA (Human Serum Albumin) and RSA (Rat Serum Albumin) antigens and biotinylated products were obtained as described in Example 1.
Affinity Maturation Libraries:
[0184] Both error prone and doped libraries were created using DOM7h-11-15 parental dAb (see SEQ ID NO: 2) as a template with arginine at position 108 mutated to tryptophan (DOM7h-11-15 R108W (DOM7h-11-55)) allowing use of trypsin for phage selection. The libraries were generated in the pDOM33 vector.
[0185] For the doped CDR libraries, primary PCR reactions were performed using doped oligonucleotides containing biased degenerated codons to diversify the required positions in the dAb. Generation of doped libraries is described, for example, in Balint and Larrick, Gene, 137, 109-118 (1993). Primers were designed in order to change only the first two nucleotides from each degenerated codon so that the parental nucleotides were present in 85% of cases and in 5% of cases all other possible nucleotides were present. Six codons per CDR were targeted for being mutated simultaneously with 15% probability per nucleotide in the codon to be different than the parental nucleotide. Assembly PCR was then used to generate a full length diversified insert. The inserts were digested with Sal I and Not I and used in a ligation reaction with pDOM33. The ligation of libraries were then used to transform E. coli strain TB1 by electroporation and the transformed cells plated on 2xTY agar containing 15 μg/ml tetracycline.
[0186] There were three doped libraries, one per each CDR and the mutation rate and libraries sizes were as follows:
[0187] CDR1 library--1.6 amino acid mutation per dAb with library size of 1.4×108
[0188] CDR2 library--1.7 amino acid mutation per dAb with library size of 2×108
[0189] CDR3 library--2 amino acid mutation per dAb with library size of 1.1×108
[0190] ii) Selection Strategies:
Selections Against HSA
[0191] Two rounds of selection against HSA were carried out. Each CDR library was selected as an individual pool in all rounds. Both rounds of selections were performed in solution against biotinylated HSA at 10 nM concentration. Libraries were eluted with 0.1M glycine pH 2.0 before neutralization with 1M Tris pH 8.0 and before infection into log phase TG1 cells. The second round of each selection was subcloned into pDOM5 for screening.
Cross Over Selection
[0192] Two rounds of selection against biotinylated SA in solution were carried out. The first round was performed against HSA at 10 nM concentration and the second round against RSA at 100 nm concentration. Each CDR library was selected as an individual pool in all rounds. Libraries were eluted with 0.1M glycine pH 2.0 before neutralization with 1M Tris pH 8.0 and before infection into log phase TG1 cells. The second round of each selection was subcloned into pDOM5 for screening.
[0193] ii) Screening Strategy and Affinity Determination
[0194] In each case after selection a pool of phage DNA from the appropriate round of selection was prepared using a QIAfilter midiprep kit (Qiagen), the DNA is digested using the restriction enzymes SalI and Not1 and the enriched V genes are ligated into the corresponding sites in pDOM5 the soluble expression vector which expresses the dAb with a myc tag (see PCT/EP2008/067789). The ligated DNA is used to transform chemically competent E. coli HB 2151 cells which are then grown overnight on agar plates containing the antibiotic carbenicillin. The resulting colonies are individually assessed for antigen binding. For each selection output, 93 clones were tested for binding to HSA, and RSA by BIAcore® (surface plasmon resonance). Soluble dAb fragments were produced in bacterial culture in ONEX culture media (Novagen) overnight at 37° C. in 96 well plates. The culture supernatant containing soluble dAb was centrifuged and analysed by BIAcore for binding to high density HSA, and RSA CM5 chips. Clones which were found to bind equally or better than parental clone to both these species of serum albumin by off-rate screening were sequenced revealing unique dAb sequences.
[0195] Unique dAbs were expressed as bacterial supernatants in 0.5 L shake flasks in Onex media at 30° C. for 48 hrs at 250 rpm. dAbs were purified from the culture media by absorption to protein L streamline followed by elution with 0.1M glycine pH2.0. To determine the binding affinity (KD) of the AlbudAbs to Human, Rat, Mouse and Cynomolgus serum albumin; purified dAbs were analysed by BIAcore over albumin concentration range from 500 nM to 3.9 nM (500 nM, 250 nM, 125 nM, 31.25 nM, 15.625 nM, 7.8125 nM, 3.90625 nM).
[0196] MSA antigen was obtained from Sigma (essentially fatty acid free, ˜99% (agarose gel electrophoresis), lyophilized powder Cat. No. A3559) and CSA was purified from Cynomolgus serum albumin using prometic blue resin (Amersham). The affinities to all tested serum albumin species of key clones is presented in Table 16.
[0197] In these assays, myc-tagged molecules were used in PK studies.
TABLE-US-00027 TABLE 16 A to D ka (1/Ms) kd (Ms) KA (1/M) KD (nM) A RSA DOM7h-11-15 21.0 DOM7h-11-56 23.4 DOM7h-11-57 5.66E+05 1.93E-02 3.42E+07 29.2 DOM7h-11-65 7.80E+05 2.04E-02 4.06E+07 24.6 DOM7h-11-67 1.33E+06 1.46E-02 8.60E+07 11.6 DOM7h-11-68 25.3 DOM7h-11-69 27.1 DOM7h-11-79 11.1 DOM7h-11-80 24.1 B HSA DOM7h-11-15 1.4 DOM7h-11-56 1.6 DOM7h-11-57 1.22E+06 1.97E-03 5.52E+08 1.8 DOM7h-11-65 1.30E+06 2.22E-03 5.52E+08 1.8 DOM7h-11-67 1.75E+06 1.65E-03 1.12E+09 0.9 DOM7h-11-68 33.5 DOM7h-11-69 3.2 DOM7h-11-79 5.9 DOM7h-11-80 2.1 C CSA DOM7h-11-15 5.3 DOM7h-11-56 5.2 DOM7h-11-57 1.34E+06 7.23E-03 1.63E+08 6.1 DOM7h-11-65 1.19E+06 7.96E-03 6.35E+07 15.7 DOM7h-11-67 2.03E+06 5.34E-03 3.69E+08 2.7 DOM7h-11-68 37.9 DOM7h-11-69 5.9 DOM7h-11-79 11.7 DOM7h-11-80 5.5 D MSA DOM7h-11-15 10.3 DOM7h-11-56 7.6 DOM7h-11-57 10.9 DOM7h-11-65 9.4 DOM7h-11-67 6.7 DOM7h-11-68 15.5 DOM7h-11-69 10.0 DOM7h-11-79 6.9 DOM7h-11-80 10.9
[0198] All DOM7h-11-15 variants are cross-reactive to rat, human, cyno and mouse serum albumin. (dissociation constant (KD); off-rate constant (KO; on-rate constant (Ka).
[0199] iv) Expression and Biophysical Characterisation:
[0200] Bacterial expression and expression by SECMALLS and DSC was carried out as described above in Example 5.
TABLE-US-00028 TABLE 17 Biophysical parameters Average Expression AlbudAb DSC Tm(° C.) SEC MALLS level (mg/l) DOM7h-11-15 53.9 T/D, Monomer 21 (R108W) DOM7h-11-56 56.1 Trimer, 10 Monomer DOM7h-11-57 58.2 Monomer 15 DOM7h-11-65 61.2 Monomer 40 DOM7h-11-67 57.2 Monomer 36 DOM7h-11-68 55.9 Monomer 12 DOM7h-11-69 57.8 Monomer 22 DOM7h-11-79 55.1 T/D, D/M, 16 Monomer DOM7h-11-80 56.2 Monomer 11
[0201] T/D and D/M indicates an equilibrium between trimer and dimer or dimer and monomer, respectively, as detected by SEC-MALLS.
[0202] All the DOM7h-11-15 variants presented in the Table 2 have favorable biophysical parameters (monomeric in solution as determined by SEC MALLs and appTm of >55° C. as determined by DSC) and expression levels were mostly maintained during affinity maturation. Thermostability is advantageous because it may improve the shelf life of the drug fused to AlbudAb with higher melting temperature when compared to Albudab with low Tm.
[0203] v) CDR3 and Framework 3 Sequences of Most Thermostable Clones
[0204] The essential differences in properties of the most thermostable AlbudAbs (appTm of >57° C.) are due to single amino acid mutations in CDR 3 or framework 3 (mutations due to polymerase error) of these clones when compared to parental clone DOM7h-11-15. Sequences of framework 3 or CDR 3 containing favorable mutations are presented in Tables 18 and 19. Amino acids that distinguish thermostable AlbudAbs from parent are in bold.
[0205] Full amino acid and nucleotide sequences of parent and all thermostable variants of DOM7h-11-15 (Tm of >55° C.) are listed in the sequences section (sequence 1-18). Most of the clones has arginine at position 108 mutated to tryptophan which was done to enable trypsin driven selection if necessary (knocking trypsin recognition site out). Mutation of isoleucine to asparagine at position 106 in DOM7h-11-67 was also included.
[0206] Other clones (see DOM 7h-11-87, DOM 7h-11-90, DOM 7h-11-86) were derived in which position 108 was back mutated to arginine (W108R) and, optionally, position 106 was back mutated to isoleucine. The sequences of these clones are listed below.
[0207] Binding to SA is summarized in the following tables:
TABLE-US-00029 HSA ka (1/Ms) kd (Ms) KA (1/M) KD (M) DOM7h-11-90 4.69E+05 8.70E-05 5.27E+07 2.02E-08 DOM7h-11-86 7.90E+05 8.83E-05 9.51E+07 1.07E-08 DOM7h-11-87 1.17E+06 1.04E-04 1.37E+08 7.39E-09 DOM7h-11-88 1.14E+06 8.12E-05 1.51E+08 6.71E-09
TABLE-US-00030 RSA ka (1/Ms) kd (Ms) KA (1/M) KD (M) DOM7h-11-90 3.76E+05 3.66E-04 1.91E+07 5.36E-08 DOM7h-11-86 5.60E+05 3.87E-04 2.80E+07 3.78E-08 DOM7h-11-87 8.30E+05 1.90E-04 5.77E+07 1.76E-08 DOM7h-11-88 8.46E+05 2.03E-04 5.96E+07 1.69E-08
TABLE-US-00031 CSA ka (1/Ms) kd (Ms) KA (1/M) KD (M) DOM7h-11-90 7.47E+05 1.31E-04 1.01E+08 9.99E-09 DOM7h-11-86 8.33E+05 1.43E-04 1.08E+08 1.34E-08 DOM7h-11-87 1.37E+06 1.23E-04 2.47E+08 4.21E-09 DOM7h-11-66 1.49E+06 1.27E-04 2.76E+08 3.65E-09
Table showing biophysical properties
TABLE-US-00032 Average Thermal expression level stability Solution AlbudAb mg/L Tm (° C.) state DOM7h-11-90 4 60 Monomer (DOM7h-11-57 W108R/N106I) DOM7h-11-86 17 61.5 Monomer (DOM7h-11-65 W108R/N106I) DOM7h-11-87 17 57.2 Monomer (DOM7h-11-67 W108R/N106I) DOM7h-11-88 16 57 Monomer (DOM7h-11-67 W108R)
TABLE-US-00033 TABLE 18 Amino acids that distinguish thermostable AlbudAbs from parent are in bold. All numbering is with reference to Kabat. Amino acid sequences CDR 3 (amino Framework 3 acid (amino acid residues AlbudAb residues 57 to 88) 89-97) DOM7h-11-15 GVPSRFSGSGSGTDFT AQAGTHPTT LTISSLQPEDFATYYC (SEQ ID (SEQ ID NO: 391) NO: 392) DOM7h-11-57 GVPSRFSGSGSGTDFT AQAGTHPTT LTISNLQPEDFATYYC (SEQ ID (SEQ ID NO: 393) NO: 394) DOM7h-11-65 GVPSRFSGSGSGTDFT AQAGTHPTT LTISSLQPEDVATYYC (SEQ ID (SEQ ID NO: 395) NO: 396) DOM7h-11-67 GVPSRFSGSGSGTDFT AQAGTHHTT LTISSLQPEDFATYYC (SEQ ID (SEQ ID NO: 397) NO: 398) DOM7h-11-69 GVPSRFSGSGSGTDFT AQAGVHPTT LTISSLQPEDFATYYC (SEQ ID (SEQ ID NO: 399) NO: 400)
TABLE-US-00034 TABLE 19 Nucleotide sequences AlbudAb Framework 3 CDR 3 DOM7h-11-15 GGGGTCCCATCACGTTTCAGTGGC GCGCAGGCT AGTGGATCTGGGACAGATTTCACT GGGACGCAT CTCACCATCAGCAGTCTGCAACCT CCTACGACG GAAGATTTTGCTACGTACTACTGC (SEQ ID (SEQ ID NO: 401) NO: 402) DOM7h-11-57 GGGGTCCCATCACGTTTCAGTGGC GCGCAGGCT AGTGGATCTGGGACAGATTTCACT GGGACGCAT CTCACCATCAGCAATCTGCAACCT CCTACGACG GAAGATTTTGCTACGTACTACTGC (SEQ ID (SEQ ID NO: 403) NO: 404) DOM7h-11-65 GGGGTCCCATCACGTTTCAGTGGC GCGCAGGCT AGTGGATCTGGGACAGATTTCACT GGGACGCAT CTCACCATCAGCAGTCTGCAACCT CCTACGACG GAAGATGTTGCTACGTACTACTGT (SEQ ID (SEQ ID NO: 405) NO: 406) DOM7h-11-67 GGGGTCCCATCACGTTTCAGTGGC GCGCAGGCT AGTGGATCTGGGACAGATTTCACT GGGACGCAT CTCACCATCAGCAGTCTGCAACCT CATACGACG GAAGATTTTGCTACGTACTACTGT (SEQ ID (SEQ ID NO: 407) NO: 408) DOM7h-11-69 GGGGTCCCATCACGTTTCAGTGGC GCGCAGGCT AGTGGATCTGGGACAGATTTCACT GGGGTGCAT CTCACCATCAGCAGTCTGCAACCT CCTACGACG GAAGATTTTGCTACGTACTACTGT (SEQ ID (SEQ ID NO: 409) NO: 410)
The mutations to DOM 7h-11-15 identified are as follows:
TABLE-US-00035 AlbudAb Mutation compared to DOM 7h-11-15 DOM7h-11-56 T22S, R108W DOM7h-11-57 S77N, R108W DOM7h-11-65 F83V, R108W DOM7h-11-67 P95H, I106N, R108W DOM7h-11-68 K42E, A91T, R108W DOM7h-11-69 T93V DOM7h-11-79 A91T, R108W DOM7h-11-80 T22F, R108W
Sequences of DOM7h-11-15 Variants
Amino Acid Sequences
TABLE-US-00036
[0208] DOM7h-11-15 R108W (DOM7h-11-55) (SEQ ID NO: 411) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLL ILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTH PTTFGQGTKVEIKW DOM7h-11-56 (SEQ ID NO: 412) DIQMTQSPSSLSASVGDRVTISCRASRPIGTMLSWYQQKPGKAPKLL ILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTH PTTFGQGTKVEIKW DOM7h-11-57 (SEQ ID NO: 413) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLL ILAFSRLQSGVPSRFSGSGSGTDFTLTISNLQPEDFATYYCAQAGTH PTTFGQGTKVEIKW DOM7h-11-65 (SEQ ID NO: 414) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLL ILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAQAGTH PTTFGQGTKVEIKW DOM7h-11-67 (SEQ ID NO: 415) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLL ILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTH HTTFGQGTKVENKW DOM7h-11-68 (SEQ ID NO: 416) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGEAPKLL ILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQTGTH PTTFGQGTKVEIKW DOM7h-11-69 (SEQ ID NO: 417) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLL ILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGVH PTTFGQGTKVEIKR DOM7h-11-79 (SEQ ID NO: 418) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLL ILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQTGTH PTTFGQGTKVEIKW DOM7h-11-80 (SEQ ID NO: 419) DIQMTQSPSSLSASVGDRVTIFCRASRPIGTMLSWYQQKPGKAPKLL ILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTH PTTFGQGTKVEIKW >DOM7h-11-90 (SEQ ID NO: 420) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLL ILAFSRLQSGVPSRFSGSGSGTDFTLTISNLQPEDFATYYCAQAGTH PTTFGQGTKVEIKR >DOM7h-11-86 (SEQ ID NO: 421) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLL ILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAQAGTH PTTFGQGTKVEIKR >DOM7h-11-87 (SEQ ID NO: 422) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLL ILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTH HTTFGQGTKVEIKR DOM7h-11-88 (SEQ ID NO: 423) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLL ILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTH HTTFGQGTKVENKR
Nucleotide Sequences
TABLE-US-00037
[0209] DOM7h-11-15 R108W (DOM7h-11-55) (SEQ ID NO: 424) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAG ACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTT AAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTT GCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTG GATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGA TTTTGCTACGTACTACTGCGCGCAGGCTGGGACGCATCCTACGACGTTC GGCCAAGGGACCAAGGTGGAAATCAAATGG DOM7h-11-56 (SEQ ID NO: 425) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAG ACCGTGTCACCATCTCTTGCCGGGCAAGTCGTCCGATTGGGACGATGTT AAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTT GCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTG GATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGA TTTTGCTACGTACTACTGCGCGCAGGCTGGGACGCATCCTACGACGTTC GGCCAAGGGACCAAGGTGGAAATCAAATGG DOM7h-11-57 (SEQ ID NO: 426) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAG ACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTT AAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTT GCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTG GATCTGGGACAGATTTCACTCTCACCATCAGCAATCTGCAACCTGAAGA TTTTGCTACGTACTACTGCGCGCAGGCTGGGACGCATCCTACGACGTTC GGCCAAGGGACCAAGGTGGAAATCAAATGG DOM7h-11-65 (SEQ ID NO: 427) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAG ACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTT AAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTT GCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTG GATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGA TGTTGCTACGTACTACTGTGCGCAGGCTGGGACGCATCCTACGACGTTC GGCCAAGGGACCAAGGTGGAAATCAAATGG DOM7h-11-67 (SEQ ID NO: 428) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAG ACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTT AAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTT GCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTG GATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGA TTTTGCTACGTACTACTGTGCGCAGGCTGGGACGCATCATACGACGTTC GGCCAAGGGACCAAGGTGGAAAACAAATGG DOM7h-11-68 (SEQ ID NO: 429) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAG ACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTT AAGTTGGTACCAGCAGAAACCAGGGGAAGCCCCTAAGCTCCTGATCCTT GCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTG GATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGA TTTTGCTACGTACTACTGTGCGCAGACTGGGACGCATCCTACGACGTTC GGCCAAGGGACCAAGGTGGAAATCAAATGG DOM7h-11-69 (SEQ ID NO: 430) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAG ACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTT AAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTT GCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTG GATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGA TTTTGCTACGTACTACTGTGCGCAGGCTGGGGTGCATCCTACGACGTTC GGCCAAGGGACCAAGGTGGAAATCAAACGG DOM7h-11-79 (SEQ ID NO: 431) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAG ACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTT AAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTT GCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTG GATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGA TTTTGCTACGTACTACTGTGCGCAGACTGGGACGCATCCTACGACGTTC GGCCAAGGGACCAAGGTGGAAATCAAATGG DOM7h-11-80 (SEQ ID NO: 432) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAG ACCGTGTCACCATCTTTTGCCGGGCAAGTCGTCCGATTGGGACGATGTT AAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTT GCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTG GATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGA TTTTGCTACGTACTACTGCGCGCAGGCTGGGACGCATCCTACGACGTTC GGCCAAGGGACCAAGGTGGAAATCAAATGG >DOM7h-11-90 (SEQ ID NO: 433) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAG ACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTT AAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTT GCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTG GATCTGGGACAGATTTCACTCTCACCATCAGCAATCTGCAACCTGAAGA TTTTGCTACGTACTACTGCGCGCAGGCTGGGACGCATCCTACGACGTTC GGCCAAGGGACCAAGGTGGAAATCAAACGG >DOM7h-11-86 (SEQ ID NO: 434) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAG ACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTT AAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTT GCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTG GATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGA TGTTGCTACGTACTACTGTGCGCAGGCTGGGACGCATCCTACGACGTTC GGCCAAGGGACCAAGGTGGAAATCAAACGG >DOM7h-11-87 (SEQ ID NO: 435) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAG ACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTT AAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTT GCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTG GATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGA TTTTGCTACGTACTACTGTGCGCAGGCTGGGACGCATCATACGACGTTC GGCCAAGGGACCAAGGTGGAAATCAAACGG DOM7h-11-88 (SEQ ID NO: 436) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAG ACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTT AAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTT GCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTG GATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGA TTTTGCTACGTACTACTGTGCGCAGGCTGGGACGCATCATACGACGTTC GGCCAAGGGACCAAGGTGGAAAACAAACGG
TABLE-US-00038 TABLE OF SEQUENCES SEQ ID No Description Amino acids Nucleotide DOM7h-11-12 amino acid 1 6 DOM7h-11-15 amino acid 2 7 DOM7h-11-18 amino acid 3 8 DOM7h-11-19 amino acid 4 9 DOM7h-11-3 nucleotide 5 10 Sequences of anti-TNFR1 11 to 158 159 to 306 dAbs DOM7h-14/Exendin-4 fusion 307 308 DMS number 7138 DOM7h-14-10/Exendin-4 309 310 fusion DMS number 7139 DOM7h-14-18/Exendin-4 311 312 fusion DMS number 7140 DOM7h-14-19/Exendin-4 313 314 fusion DMS number 7141 DOM7h-11/Exendin-4 fusion 315 316 DMS number 7142 DOM7h-11-12/Exendin-4 317 318 fusion DMS number 7147 DOM7h-11-15/Exendin-4 319 320 fusion DMS number 7143 DOM7h14-10/G4SC-NCE 321 322 fusion DOM7h14-10/TVAAPSC 323 324 fusion DOM7h-11/DOM1m- 325 327 21-23 fusion DMS number 5515 DOM7h-11/DOM1m- 326 328 21-23 fusion DMS number 5515 plus myc tag DOM7h-11- 329 331 12/DOM1m-21-23 fusion DMS number 5516 DOM7h-11- 330 332 12/DOM1m-21-23 fusion DMS number 5516 plus myc tag DOM7h-11- 333 335 15/DOM1m-21-23 fusion DMS number 5517 DOM7h-11- 334 336 15/DOM1m-21-23 fusion DMS number 5517 plus myc tag DPK9 Vk dummy 337-339 CDRs DOM7h-11 CDRs 340-342 DOM7h-11-12 CDRs 343-345 DOM 7h-11-15 346-348 CDRs DOM 7h-11-18 349-351 CDRs DOM 7h-11-19 352-354 CDRs DOM 7h-11-3 CDRs 355-357 DOM 7h-14 CDRs 358-360 DOM 7h-14-10 361-363 CDRs DOM 7h-14-18 364-366 CDRs DOM 7h-14-19 367-369 CDRs DOM 7h-14-28 370-372 CDRs DOM 7h-14-36 373-375 CDRs Interferon alpha 2b 376 377 IFNα2b SOE 378 fragment 5' IFNα2b SOE 379 fragment 3' Vk SOE fragment 5' 380 Vk SOE fragment 3' 381 to also introduce a myc tag IFNα2b SOE fragment 5' 382 Vk SOE fragment 3' to also 383 introduce a myc tag Leader sequence 384 385 DOM7h-14 R108C 386 387 DOM7h-11-15.sup.S12P 388 389 primer sequence 390 FR3 and CDR3 sequences 391 to 400 401 to 410 for thermostable variants DOM7h-11-15 R108W 411 424 DOM7h-11-56 412 425 DOM7h-11-57 413 426 DOM7h-11-65 414 427 DOM7h-11-67 415 428 DOM7h-11-68 416 429 DOM7h-11-69 417 430 DOM7h-11-79 418 431 DOM7h-11-80 419 432 DOM7h-11-90 420 433 DOM7h-11-86 421 434 DOM7h-11-87 422 435 DOM7h-11-88 423 436 Linker sequence 437 DOM7h-11 438
Sequence CWU
1
1
4401108PRTHomo sapiens 1Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
Ala Ser Val Gly1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro Ile Gly Thr Met
20 25 30 Leu Ser Trp Tyr
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35
40 45 Leu Phe Gly Ser Arg Leu Gln Ser Gly
Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
Gln Pro65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His Pro Thr
85 90 95 Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys Arg 100 105
2108PRTHomo sapiens 2Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro Ile Gly Thr Met
20 25 30 Leu Ser Trp Tyr Gln
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40
45 Leu Ala Phe Ser Arg Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro65 70 75 80 Glu
Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His Pro Thr
85 90 95 Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg 100 105
3108PRTHomo sapiens 3Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro Ile Gly Thr Met
20 25 30 Leu Ser Trp Tyr Gln
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40
45 Trp Phe Gly Ser Arg Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro65 70 75 80 Glu
Asp Phe Ala Thr Tyr His Cys Ala Gln Ala Gly Thr His Pro Thr
85 90 95 Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg 100 105
4108PRTHomo sapiens 4Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro Ile Gly Thr Met
20 25 30 Leu Ser Trp Tyr Gln
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40
45 Leu Phe Gly Ser Arg Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro65 70 75 80 Glu
Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Thr Gly Thr His Pro Thr
85 90 95 Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg 100 105
5108PRTHomo sapiens 5Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro Ile Gly Thr Thr
20 25 30 Leu Ser Trp Tyr Gln
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40
45 Leu Trp Asn Ser Arg Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro65 70 75 80 Glu
Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His Pro Thr
85 90 95 Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg 100 105
6324DNAArtificial SequenceNucleotide 6gacatccaga tgacccagtc tccatcctcc
ctgtctgcat ctgtaggaga ccgtgtcacc 60atcacttgcc gggcaagtcg tccgattggg
acgatgttaa gttggtacca gcagaaacca 120gggaaagccc ctaagctcct gatcttgttt
ggttcccggt tgcaaagtgg ggtcccatca 180cgtttcagtg gcagtggatc tgggacagat
ttcactctca ccatcagcag tctgcaacct 240gaagattttg ctacgtacta ctgtgcgcag
gctgggacgc atcctacgac gttcggccaa 300gggaccaagg tggaaatcaa acgg
3247324DNAArtificial SequenceNucleotide
7gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga ccgtgtcacc
60atcacttgcc gggcaagtcg tccgattggg acgatgttaa gttggtacca gcagaaacca
120gggaaagccc ctaagctcct gatccttgct ttttcccgtt tgcaaagtgg ggtcccatca
180cgtttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct
240gaagattttg ctacgtacta ctgcgcgcag gctgggacgc atcctacgac gttcggccaa
300gggaccaagg tggaaatcaa acgg
3248324DNAArtificial SequenceNucleotide 8gacatccaga tgacccagtc tccatcctcc
ctgtctgcat ctgtaggaga ccgtgtcacc 60atcacttgcc gggcaagtcg tccgattggg
acgatgttaa gttggtacca gcagaaacca 120gggaaagccc ctaagctcct gatcttgttt
ggttcccggt tgcaaagtgg ggtcccatca 180cgtttcagtg gcagtggatc tgggacggat
ttcactctca ccatcagcag tctgcaacct 240gaagattttg ctacgtacta ctgtgcgcag
actgggacgc atcccacgac gttcggccaa 300gggaccaagg tggaaatcaa acgg
3249324DNAArtificial SequenceNucleotide
9gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga ccgtgtcacc
60atcacttgcc gggcaagtcg tccgattggg acgacgttaa gttggtacca gcagaaacca
120gggaaagccc ctaagctcct gatcctttgg aattcccgtt tgcaaagtgg ggtcccatca
180cgtttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct
240gaagattttg ctacgtacta ctgtgcgcag gctgggacgc atcctacgac gttcggccaa
300gggaccaagg tggaaatcaa acgg
32410324DNAArtificial SequenceNucleotide 10gacatccaga tgacccagtc
tccatcctcc ctgtctgcat ctgtaggaga ccgtgtcacc 60atcacttgcc gggcaagtcg
tccgattggg acgacgttaa gttggtacca gcagaaacca 120gggaaagccc ctaagctcct
gatcctttgg aattcccgtt tgcaaagtgg ggtcccatca 180cgtttcagtg gcagtggatc
tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg ctacgtacta
ctgtgcgcag gctgggacgc atcctacgac gttcggccaa 300gggaccaagg tggaaatcaa
acgg 32411120PRTHomo sapiens
11Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gln Tyr 20
25 30 Arg Met His Trp Val Arg Gln Ala Pro
Gly Lys Ser Leu Glu Trp Val 35 40
45 Ser Ser Ile Asp Thr Arg Gly Ser Ser Thr Tyr Tyr Ala Asp
Pro Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys Ala Val Thr Met Phe Ser Pro Phe
Phe Asp Tyr Trp Gly Gln 100 105
110 Gly Thr Leu Val Thr Val Ser Ser 115
120 12123PRTHomo sapiens 12Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Tyr
20 25 30 Gly Met Arg
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Ser Ile Thr Arg Thr Gly Arg
Val Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
Thr Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Lys Trp Arg Asn
Arg His Gly Glu Tyr Leu Ala Asp Phe Asp Tyr 100
105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 13120PRTHomo sapiens 13Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Met Arg Tyr 20 25
30 Arg Met His Trp Val Arg Gln Ala Pro Gly Lys
Gly Leu Glu Trp Val 35 40 45
Ser Ser Ile Asp Ser Asn Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60 Lys Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Lys Asp Arg Thr Glu Arg Ser Pro Val Phe Asp Tyr
Trp Gly Gln 100 105 110
Gly Thr Leu Val Thr Val Ser Ser 115 120
14119PRTHomo sapiens 14Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Asp Tyr
20 25 30 Glu Met His Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Ser Ile Ser Glu Ser Gly Thr Thr
Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Lys Arg Arg Phe
Ser Ala Ser Thr Phe Asp Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
15119PRTHomo sapiens 15Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn
Thr Gly Gly His Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Lys Tyr Thr Gly His Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 16119PRTHomo sapiens 16Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ser Asn Thr Gly Gly His Thr Tyr Tyr Ala Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Lys Tyr Thr Gly Arg Trp Glu Pro Tyr Asp Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 17119PRTHomo sapiens
17Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Gly Gly His Thr Tyr Tyr Ala Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys Tyr Thr Gly Arg Trp Glu Pro Phe
Asp Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
18119PRTHomo sapiens 18Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn Thr Gly Gly His
Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
19119PRTHomo sapiens 19Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn
Thr Gly Gly His Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 20119PRTHomo sapiens 20Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ser Asn Thr Gly Gly His Thr Tyr Tyr Ala Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Met Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 21119PRTHomo sapiens
21Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Asp Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Gly Gly His Thr Tyr Tyr Ala Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe
Asp Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
22119PRTHomo sapiens 22Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Asp Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn Thr Gly Gly His
Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
23119PRTHomo sapiens 23Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn
Thr Gly Asp His Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Lys Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 24119PRTHomo sapiens 24Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Lys Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 25119PRTHomo sapiens
25Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Ala Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe
Asp Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
26119PRTHomo sapiens 26Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn Thr Gly Asp His
Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
27119PRTHomo sapiens 27Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn
Thr Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 28119PRTHomo sapiens 28Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu
Trp Val 35 40 45
Ser Gln Ile Ser Asn Thr Gly Asp His Thr Tyr Tyr Ala Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 29119PRTHomo sapiens
29Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Asp Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Ala Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe
Asp Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
30119PRTHomo sapiens 30Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Asp Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn Thr Gly Asp His
Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
31119PRTHomo sapiens 31Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn
Thr Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 32119PRTHomo sapiens 32Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 33119PRTHomo sapiens
33Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Ala Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Lys Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
34119PRTHomo sapiens 34Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn Thr Gly Asp Arg
Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
35119PRTHomo sapiens 35Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn
Thr Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 36119PRTHomo sapiens 36Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Ala Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 37119PRTHomo sapiens
37Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe
Asn Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
38119PRTHomo sapiens 38Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn Thr Gly Asp Arg
Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
39119PRTHomo sapiens 39Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn
Thr Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Ser Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Val Pro Phe Asp Asn Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 40119PRTHomo sapiens 40Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ile Thr Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Gln Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 41119PRTHomo sapiens
41Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Ala Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe
Asp Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
42119PRTHomo sapiens 42Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn Thr Gly Asp Arg
Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
43119PRTHomo sapiens 43Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp
Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 44119PRTHomo sapiens 44Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ser Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ala Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 45119PRTHomo sapiens
45Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Ala Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe
Lys Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
46119PRTHomo sapiens 46Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn Thr Gly Glu Arg
Arg Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Glu Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
47119PRTHomo sapiens 47Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Asn Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn
Thr Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Glu Pro Tyr Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Thr Ser 115 48119PRTHomo sapiens 48Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 49119PRTHomo sapiens
49Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Lys Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
50119PRTHomo sapiens 50Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ala Asn Thr Gly Asp Arg
Arg Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
51119PRTHomo sapiens 51Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ala Asn
Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 52119PRTHomo sapiens 52Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 53119PRTHomo sapiens
53Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Val Tyr Thr Gly Arg Trp Glu Pro Phe
Val Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
54119PRTHomo sapiens 54Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn Thr Ala Asp Arg
Thr Tyr Tyr Ala His Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Lys Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
55119PRTHomo sapiens 55Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn
Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 56119PRTHomo sapiens 56Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 57119PRTHomo sapiens
57Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
58119PRTHomo sapiens 58Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Gly Asp Arg
Arg Tyr Tyr Asp Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
59119PRTHomo sapiens 59Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp
Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Lys Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 60119PRTHomo sapiens 60Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 61119PRTHomo sapiens
61Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Arg Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
62119PRTHomo sapiens 62Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Gly Asp Arg
Arg Tyr Tyr Asp Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
63119PRTHomo sapiens 63Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn
Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ala Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 64119PRTHomo sapiens 64Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ser Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ala Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Lys Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 65119PRTHomo sapiens
65Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp
Ala Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
66119PRTHomo sapiens 66Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn Thr Gly Asp Arg
Arg Tyr Tyr Ala Asp Ala Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
67119PRTHomo sapiens 67Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn
Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ala Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 68119PRTHomo sapiens 68Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Leu Lys Phe 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 69119PRTHomo sapiens
69Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
70119PRTHomo sapiens 70Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Gly Asp Arg
Arg Tyr Tyr Asp Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
71119PRTHomo sapiens 71Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp
Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 72119PRTHomo sapiens 72Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Ala Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Pro Asp Phe Asp Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 73119PRTHomo sapiens
73Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Ala Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Pro Asp Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
74119PRTHomo sapiens 74Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn Thr Ala Asp Arg
Thr Tyr Tyr Ala His Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Pro Asp Phe Asp Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
75119PRTHomo sapiens 75Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn
Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Pro Asp Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 76119PRTHomo sapiens 76Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Pro Asp Phe Asp Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 77119PRTHomo sapiens
77Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Pro Asp Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
78119PRTHomo sapiens 78Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val 35
40 45 Ser Gln Ile Ser Ala Trp Gly Asp Arg
Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
79119PRTHomo sapiens 79Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp
Gly Gly Gln Arg Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 80119PRTHomo sapiens 80Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu
Trp Val 35 40 45
Ser Gln Ile Ser Asp Ser Gly Tyr Arg Thr Tyr Tyr Ala Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 81119PRTHomo sapiens
81Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Pro Glu Trp Val 35 40
45 Ser Gln Ile Ser Asp Gly Gly Thr Arg Thr Tyr Tyr Ala Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe
Asp Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
82119PRTHomo sapiens 82Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Lys Gly Thr Arg
Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
83119PRTHomo sapiens 83Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val 35
40 45 Ser Gln Ile Ser Glu
Thr Gly Arg Arg Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 84119PRTHomo sapiens 84Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Asn Asn Thr Gly Ser Thr Thr Tyr Tyr Ala Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 85119PRTHomo sapiens
85Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Pro Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
86119PRTHomo sapiens 86Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn Thr Ala Asp Arg
Thr Tyr Tyr Ala His Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
87119PRTHomo sapiens 87Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp
Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 88119PRTHomo sapiens 88Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 89119PRTHomo sapiens
89Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Asp Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Arg Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
90119PRTHomo sapiens 90Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Ala Asp Arg
Thr Tyr Tyr Thr His Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
91119PRTHomo sapiens 91Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn
Thr Ala Asp Arg Arg Tyr Tyr Ala His Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 92119PRTHomo sapiens 92Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Leu Asn Thr Ala Asp Arg Thr Tyr Tyr Asp His Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 93119PRTHomo sapiens
93Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Asp His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
94119PRTHomo sapiens 94Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Ala Asp Arg
Arg Tyr Tyr Ala His Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
95119PRTHomo sapiens 95Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp
Thr Ala Asp Arg Arg Tyr Tyr Asp His Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 96119PRTHomo sapiens 96Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45
Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Val Tyr Thr Gly Arg Trp Val Ser Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 97119PRTHomo sapiens
97Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Leu Tyr Thr Gly Arg Trp Val Ser Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
98119PRTHomo sapiens 98Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn Thr Ala Asp Arg
Thr Tyr Tyr Ala His Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Val Tyr Thr Gly
Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
99119PRTHomo sapiens 99Glu Val Gln Leu Leu Glu Ser Gly Gly
Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val
Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn
Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95 Ala
Leu Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 100119PRTHomo sapiens 100Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45
Ser Gln Ile Ala Asn Thr Ala Asp Arg Arg Tyr Tyr Ala His Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 101119PRTHomo sapiens
101Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Ala Asp Arg Arg Tyr Tyr Ala Asp
Ala Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe
Val Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
102119PRTHomo sapiens 102Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asn Thr Gly Asp Arg
Arg Tyr Tyr Ala His Ala Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
103119PRTHomo sapiens 103Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Val Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Gln Ile Ala
Asn Thr Ala Asp Arg Arg Tyr Tyr Ala Asp Ala Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95
Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 104119PRTHomo sapiens 104Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45
Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala His Ala Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 105119PRTHomo sapiens
105Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Ala Asp Arg Arg Tyr Tyr Ala His
Ala Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe
Val Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
106119PRTHomo sapiens 106Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ala Asn Thr Ala Asp Arg
Arg Tyr Tyr Ala His Ala Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
107119PRTHomo sapiens 107Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Val Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Gln Ile Val
Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ala Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95
Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 108119PRTHomo sapiens 108Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45
Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ala Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 109119PRTHomo sapiens
109Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
110119PRTHomo sapiens 110Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Ala Asp Arg
Thr Tyr Tyr Asp His Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
111119PRTHomo sapiens 111Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Val Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Gln Ile Ser
Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95
Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 112119PRTHomo sapiens 112Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45
Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ser His Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 113119PRTHomo sapiens
113Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Thr His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
114119PRTHomo sapiens 114Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Ala Asp Arg
Thr Tyr Tyr Thr Asp Ala Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
115119PRTHomo sapiens 115Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Phe Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Gln Ile Ser
Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95
Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 116119PRTHomo sapiens 116Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Leu Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45
Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 117119PRTHomo sapiens
117Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ala Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe
Val Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
118119PRTHomo sapiens 118Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Ala Asp Arg
Arg Tyr Tyr Asp Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
119119PRTHomo sapiens 119Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Phe Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Gln Ile Ser
Asp Thr Gly Asp Arg Arg Tyr Tyr Asp His Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95
Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 120119PRTHomo sapiens 120Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Phe Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45
Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ala Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 121119PRTHomo sapiens
121Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ala Asp Thr Ala Asp Arg Arg Tyr Tyr Asp Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe
Val Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
122119PRTHomo sapiens 122Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ala Asp Thr Gly Asp Arg
Arg Tyr Tyr Asp His Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
123119PRTHomo sapiens 123Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Phe Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Gln Ile Ala
Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ala Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95
Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 124119PRTHomo sapiens 124Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45
Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Gly Pro Phe Val Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 125119PRTHomo sapiens
125Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe
Ala Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
126119PRTHomo sapiens 126Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Ala Asp Arg
Thr Tyr Tyr Ala His Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Gly Pro Phe Gln Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
127119PRTHomo sapiens 127Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Val Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Gln Ile Ser
Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95
Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Gln Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 128119PRTHomo sapiens 128Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45
Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 129119PRTHomo sapiens
129Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe
Gln Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
130119PRTHomo sapiens 130Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Ala Asp Arg
Thr Tyr Tyr Ala His Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Val Pro Phe Gln Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
131119PRTHomo sapiens 131Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Val Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Gln Ile Ser
Asp Thr Gly Asp Arg Arg Tyr Tyr Asp His Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95
Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 132119PRTHomo sapiens 132Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Leu Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45
Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 133119PRTHomo sapiens
133Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
134119PRTHomo sapiens 134Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Ala Asp Arg
Thr Tyr Tyr Asp His Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
135119PRTHomo sapiens 135Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Phe Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Gln Ile Ser
Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95
Ala Ile Tyr Thr Gly Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 136119PRTHomo sapiens 136Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Phe Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45
Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 137119PRTHomo sapiens
137Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe
Val Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
138119PRTHomo sapiens 138Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Ala Asp Arg
Thr Tyr Tyr Ser His Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
139119PRTHomo sapiens 139Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Phe Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Gln Ile Ser
Asp Thr Ala Asp Arg Thr Tyr Tyr Ser His Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95
Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 140119PRTHomo sapiens 140Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Phe Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45
Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Thr His Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 141119PRTHomo sapiens
141Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Thr His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
142119PRTHomo sapiens 142Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Ala Asp Arg
Thr Tyr Tyr Ala His Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
143119PRTHomo sapiens 143Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Leu Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Gln Ile Ser
Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95
Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 144119PRTHomo sapiens 144Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Leu Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45
Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp His Ser Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 145119PRTHomo sapiens
145Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ala Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
146119PRTHomo sapiens 146Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Ala Asp Arg
Thr Tyr Tyr Ala His Ala Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
147119PRTHomo sapiens 147Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Val Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Gln Ile Ala
Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95
Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 148119PRTHomo sapiens 148Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45
Ser Gln Ile Ala Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His Ala Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 149119PRTHomo sapiens
149Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ala Asp Thr Ala Asp Arg Arg Tyr Tyr Ala His
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
150119PRTHomo sapiens 150Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Ala Asp Arg
Arg Tyr Tyr Ala His Ala Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
151119PRTHomo sapiens 151Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Val Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Gln Ile Ala
Asp Thr Ala Asp Arg Arg Tyr Tyr Ala His Ala Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95
Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 152119PRTHomo sapiens 152Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45
Ser Gln Ile Ser Asp Thr Ala Asp Arg Arg Tyr Tyr Asp His Ala Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 153119PRTHomo sapiens
153Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ala Asp Thr Ala Asp Arg Arg Tyr Tyr Asp His
Ala Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
154119PRTHomo sapiens 154Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ala Asp Thr Ala Asp Arg
Arg Tyr Tyr Asp His Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
155119PRTHomo sapiens 155Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Phe Lys Tyr 20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Gln Ile Ser
Asp Thr Ala Asp Arg Arg Tyr Tyr Asp Asp Ala Val 50 55
60 Lys Gly Arg Phe Thr Ile Thr Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95
Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
100 105 110 Thr Leu Val Thr Val
Ser Ser 115 156119PRTHomo sapiens 156Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Val Lys Tyr 20 25
30 Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45
Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val 50
55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70
75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln
Gly 100 105 110 Thr
Leu Val Thr Val Ser Ser 115 157119PRTHomo sapiens
157Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr 20
25 30 Ser Met Gly Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Gln Ile Ser Asn Thr Gly Gly His Thr Tyr Tyr Ala Asp
Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80 Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys Tyr Thr Gly Arg Trp Glu Pro Phe
Glu Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115
158119PRTHomo sapiens 158Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
20 25 30 Ser Met Gly Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Gln Ile Ser Asp Thr Gly Asp Arg
Arg Tyr Tyr Asp His Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Ile Tyr Thr Gly
Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly 100
105 110 Thr Leu Val Thr Val Ser Ser 115
159360DNAArtificial SequenceNucleotide 159gaggtgcagc
tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag
cctccggatt cacctttagt cagtatagga tgcattgggt ccgccaggct 120ccagggaaga
gtctagagtg ggtctcaagt attgatacta ggggttcgtc tacatactac 180gcagaccccg
tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga
acagcctgcg tgccgaggac accgcggtat attactgtgc gaaagctgtg 300acgatgtttt
ctcctttttt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc
360160369DNAArtificial SequenceNucleotide 160gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgct gattatggga tgcgttgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcatct attacgcgga ctggtcgtgt tacatactac 180gcagactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gaaatggcgg 300aatcggcatg gtgagtatct
tgctgatttt gactactggg gtcagggaac cctggtcacc 360gtctcgagc
369161360DNAArtificial
SequenceNucleotide 161gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttatg aggtatagga
tgcattgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcatcg attgattcta
atggttctag tacatactac 180gcagactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gaaagatcgt 300acggagcgtt cgccggtttt tgactactgg ggtcagggaa
ccctggtcac cgtctcgagc 360162357DNAArtificial SequenceNucleotide
162gaggtgcagc tgttggagtc tgggggaggc ttggtgcagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt gattatgaga tgcattgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcatct attagtgaga gtggtacgac gacatactac
180gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacgtcgt
300ttttctgctt ctacgtttga ctactggggt cagggaaccc tggtcaccgt ctcgagc
357163357DNAArtificial SequenceNucleotide 163gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcgaata cgggtggtca tacatactac 180gcagactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gaaatatacg 300ggtcattggg agccttttga
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357164357DNAArtificial
SequenceNucleotide 164gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
cgggtggtca tacatactac 180gcagactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gaaatatacg 300ggtcgttggg agccttatga ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357165357DNAArtificial SequenceNucleotide
165gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata cgggtggtca tacatactac
180gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatatacg
300ggtcgttggg agccttttga ctactggggt cagggaaccc tggtcaccgt ctcgagc
357166357DNAArtificial SequenceNucleotide 166gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcgaata cgggtggtca tacatactac 180gcagactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gaaatatacg 300ggtcgttggg agccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357167357DNAArtificial
SequenceNucleotide 167gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ctgctgatcg tacatactac 180gcacacgcgg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgctgaggac accgcggtat
attactgtgc gatatatact 300gggcgttggg tgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357168357DNAArtificial SequenceNucleotide
168gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata cgggtggtca tacatactac
180gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttga ctactggggt cagggaaccc tggtcaccgt ctcgagc
357169357DNAArtificial SequenceNucleotide 169gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tgggatgggt ccgccaggct 120ccagggaaag gtccagagtg
ggtctcacag atttcgaata cgggtggtca tacatactac 180gcagactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttga
ctactggggt cagggaaccc tggtcacagt ctcgagc 357170357DNAArtificial
SequenceNucleotide 170gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
cgggtggtca tacatactac 180gcagactccg tgaagggccg gttcaccata tcccgcgaca
attccaagaa cacgctgtat 240atgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttga ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357171357DNAArtificial SequenceNucleotide
171gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttggt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg atctagagtg ggtctcacag atttcgaata cgggtggtca tacatactac
180gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttga ctactggggt cagggaaccc tggtcaccgt ctcgagc
357172357DNAArtificial SequenceNucleotide 172gaggtgcagc tgttggagtc
agggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcgaata cgggtggtca tacatactac 180gcagactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gaaatatacg 300ggtcgttggg agccttttga
ccactggggt caggggaccc tggtcaccgt ctcgagc 357173357DNAArtificial
SequenceNucleotide 173gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
cgggtgatca tacatactac 180gcagactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gaaatatacg 300ggtcgttggg agccttttga ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357174357DNAArtificial SequenceNucleotide
174gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata cgggtgatcg tacatactac
180gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatatacg
300ggtcgttggg agccttttga ctactggggt cagggaaccc tggtcaccgt ctcgagc
357175357DNAArtificial SequenceNucleotide 175gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcgaata cgggtgatcg tacatactac 180gcagactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttga
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357176357DNAArtificial
SequenceNucleotide 176gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
cgggtgatca tacatactac 180gcagactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttga ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357177357DNAArtificial SequenceNucleotide
177gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tgggatgggt ccgccaggct
120ccagggaaag gtccagagtg ggtctcacag atttcgaata cgggtgatcg tacatactac
180gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttga ctactggggt cagggaaccc tggtcacagt ctcgagc
357178357DNAArtificial SequenceNucleotide 178gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tgggatgggt ccgccaggct 120ccagggaaag gtccagagtg
ggtctcacag atttcgaata cgggtgatca tacatactac 180gcagactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttga
ctactggggt cagggaaccc tggtcacagt ctcgagc 357179357DNAArtificial
SequenceNucleotide 179gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttggt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg atctagagtg ggtctcacag atttcgaata
cgggtgatcg tacatactac 180gcagactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttga ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357180357DNAArtificial SequenceNucleotide
180gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttggt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg atctagagtg ggtctcacag atttcgaata cgggtgatca tacatactac
180gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttga ctactggggt cagggaaccc tggtcaccgt ctcgagc
357181357DNAArtificial SequenceNucleotide 181gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcgaata cgggtgatcg tacatactac 180gcagactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttgt
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357182357DNAArtificial
SequenceNucleotide 182gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
cgggtgatcg tacatactac 180gcagactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgctgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357183357DNAArtificial SequenceNucleotide
183gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata cgggtgatcg tacatactac
180gcggactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgctgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttgga agccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357184357DNAArtificial SequenceNucleotide 184gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcgaata cgggtgatcg tacatactac 180gcagactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgctgaggac accgcggtat attactgtgc gatatatact 300gggcgttggg tgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357185357DNAArtificial
SequenceNucleotide 185gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
cgggtgatcg tacatactac 180gcagactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttgga ggccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357186357DNAArtificial SequenceNucleotide
186gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag attgcgaata cgggtgatcg tagatactac
180gcagactctg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggcat attactgtgc gatatatacg
300ggtcgttggg agccttttga ctactggggt cagggaaccc tggtcaccgt ctcgagc
357187357DNAArtificial SequenceNucleotide 187gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcgaata ctgctgatcg tacatactac 180gcacactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttaa
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357188357DNAArtificial
SequenceNucleotide 188gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
cgggtgatcg tacatactac 180gcagactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcggtggg cgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357189357DNAArtificial SequenceNucleotide
189gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata cgggtgatcg tacatactac
180gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa ctcgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg tgccttttga caactggggt cagggaaccc tggtcaccgt ctcgagc
357190357DNAArtificial SequenceNucleotide 190gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttatt acgtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcgaata cgggtgatcg tacatactac 180gcagactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttca
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357191357DNAArtificial
SequenceNucleotide 191gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttggt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
cgggtgatcg tacatactac 180gcggactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttga ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357192357DNAArtificial SequenceNucleotide
192gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttttt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata cgggtgatcg tacatactac
180gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaagac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttga ctactggggt cagggaaccc tggtcaccgt ctcgagc
357193357DNAArtificial SequenceNucleotide 193gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata cgggtgatcg tagatactac 180gatgactctg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttga
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357194357DNAArtificial
SequenceNucleotide 194gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
cgggtgatcg tagatactac 180gcagacgcgg tgaaggggcg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttga ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357195357DNAArtificial SequenceNucleotide
195gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata cgggtgatcg tacatactac
180gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgctgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttaa gtactggggt cagggaaccc tggtcaccgt ctcgagc
357196357DNAArtificial SequenceNucleotide 196gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttagt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcgaata cgggtgagcg tagatactac 180gcagactcag tgaagggccg
gttcaccatc tcccgcgaca atcccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcggtggg agccttttga
atactggggt cagggaaccc tggtcaccgt ctcgagc 357197357DNAArtificial
SequenceNucleotide 197gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aactattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
cgggtgatcg tacatactac 180gcggactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttatga gtactggggt cagggaaccc
tggtcaccgt cacgagc 357198357DNAArtificial SequenceNucleotide
198gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag attgcgaata cgggtgatcg tagatactac
180gcagactctg tgaagggccg gttcaccatc tcccgcgata attccaagaa cacactgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttgt ctactggggt cagggaaccc tggtcaccgt ctcgagc
357199357DNAArtificial SequenceNucleotide 199gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag attgcgaata cgggtgatcg tagatactac 180gcagactctg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttgga agccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357200357DNAArtificial
SequenceNucleotide 200gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag attgcgaata
cgggtgatcg tagatactac 180gcagactctg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgctgaggac accgcggtat
attactgtgc gatatatact 300gggcgttggg tgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357201357DNAArtificial SequenceNucleotide
201gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag attgcgaata cgggtgatcg tagatactac
180gcagactctg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttgga ggccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357202357DNAArtificial SequenceNucleotide 202gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag attgcgaata cgggtgatcg tagatactac 180gcagactctg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcggtggg cgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357203357DNAArtificial
SequenceNucleotide 203gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
ctgctgatcg tacatactac 180gcacactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc ggtatatacg 300ggtcgttggg agccttttgt ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357204357DNAArtificial SequenceNucleotide
204gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata ctgctgatcg tacatactac
180gcacactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgctgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttgga agccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357205357DNAArtificial SequenceNucleotide 205gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcgaata ctgctgatcg tacatactac 180gcacactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgctgaggac accgcggtat attactgtgc gatatatact 300gggcgttggg tgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357206357DNAArtificial
SequenceNucleotide 206gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
ctgctgatcg tacatactac 180gcacactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttgga ggccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357207357DNAArtificial SequenceNucleotide
207gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata ctgctgatcg tacatactac
180gcacactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcggtggg cgccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357208357DNAArtificial SequenceNucleotide 208gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata cgggtgatcg tagatactac 180gatgactctg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttgt
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357209357DNAArtificial
SequenceNucleotide 209gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggcc 120ccagggaagg gtctagagtg ggtctcacag atttcggata
cgggtgatcg tagatactac 180gatgactctg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgctgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttgga agccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357210357DNAArtificial SequenceNucleotide
210gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcggata cgggtgatcg tagatactac
180gatgactctg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatact
300gggcgttggg tgccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357211357DNAArtificial SequenceNucleotide 211gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata cgggtgatcg tagatactac 180gatgactctg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttgga ggccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357212357DNAArtificial
SequenceNucleotide 212gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
cgggtgatcg tagatactac 180gatgactctg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcggtggg cgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357213357DNAArtificial SequenceNucleotide
213gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata cgggtgatcg tagatactac
180gcagacgcgg tgaaggggcg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttgt ctactggggt cagggaaccc tggtcaccgt ctcgagc
357214357DNAArtificial SequenceNucleotide 214gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcgaata cgggtgatcg tagatactac 180gcagacgcgg tgaaggggcg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgctgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttgga agccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357215357DNAArtificial
SequenceNucleotide 215gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggcc 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
cgggtgatcg tagatactac 180gcagacgcgg tgaaggggcg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaagac accgcggtat
attactgtgc gatatatact 300gggcgttggg tgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357216357DNAArtificial SequenceNucleotide
216gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata cgggtgatcg tagatactac
180gcagacgcgg tgaaggggcg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttgga ggccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357217357DNAArtificial SequenceNucleotide 217gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcgaata cgggtgatcg tagatactac 180gcagacgcgg tgaaggggcg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcggtggg cgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357218357DNAArtificial
SequenceNucleotide 218gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttttg aagttttcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag attgcgaata
cgggtgatcg tagatactac 180gcagactctg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcggtggg cgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357219357DNAArtificial SequenceNucleotide
219gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttttg aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata ctgctgatcg tacatactac
180gcacactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcggtggg cgccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357220357DNAArtificial SequenceNucleotide 220gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttttc aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata cgggtgatcg tagatactac 180gatgactctg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttgt
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357221357DNAArtificial
SequenceNucleotide 221gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttttg aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
cgggtgatcg tagatactac 180gatgactctg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttgt ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357222357DNAArtificial SequenceNucleotide
222gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag attgcgaata cgggtgatcg tagatactac
180gcagactctg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggcat attactgtgc gatatatacg
300ggtcggtggc ccgactttga ctactggggt cagggaaccc tggtcaccgt ctcgagc
357223357DNAArtificial SequenceNucleotide 223gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag attgcgaata cgggtgatcg tagatactac 180gcagactctg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggcat attactgtgc gatatatacg 300ggtcggtggc ccgactttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357224357DNAArtificial
SequenceNucleotide sequences of anti-TNFR1 dAbs 224gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcgaata ctgctgatcg tacatactac 180gcacactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcggtggc ccgactttga
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357225357DNAArtificial
SequenceNucleotide 225gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
ctgctgatcg tacatactac 180gcacactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcggtggc ccgactttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357226357DNAArtificial SequenceNucleotide
226gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcggata cgggtgatcg tagatactac
180gatgactctg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcggtggc ccgactttga ctactggggt cagggaaccc tggtcaccgt ctcgagc
357227357DNAArtificial SequenceNucleotide 227gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata cgggtgatcg tagatactac 180gatgactctg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcggtggc ccgactttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357228357DNAArtificial
SequenceNucleotide 228gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tgggatgggt ccgccaggct 120ccagggaaag gtccagagtg ggtctcacag atttcggcct
ggggtgacag gacatactac 180gcagactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttga ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357229357DNAArtificial SequenceNucleotide
229gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaaag gtccagagtg ggtctcacag atttcggacg gcggtcagag gacatactac
180gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttga ctactggggt cagggaaccc tggtcaccgt ctcgagc
357230357DNAArtificial SequenceNucleotide 230gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tgggatgggt ccgccaggct 120ccagggaaag gtccagagtg
ggtctcacag atttcggact ccggttaccg cacatactac 180gcagactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttga
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357231357DNAArtificial
SequenceNucleotide 231gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtccagagtg ggtctcacag atttcggacg
ggggtacgcg gacatactac 180gcagactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttga ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357232357DNAArtificial SequenceNucleotide
232gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tgggatgggt ccgccaggct
120ccagggaaag gtccagagtg ggtctcacag atttcggaca agggtacgcg cacatactac
180gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttga ctactggggt cagggaaccc tggtcaccgt ctcgagc
357233357DNAArtificial SequenceNucleotide 233gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tgggatgggt ccgccaggct 120ccagggaaag gtccagagtg
ggtctcacag atttcggaga ccggtcgcag gacatactac 180gcagactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttga
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357234357DNAArtificial
SequenceNucleotide 234gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag attaacaata
cgggttcgac cacatactac 180gcagactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttga ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357235357DNAArtificial SequenceNucleotide
sequences of anti-TNFR1 dAbs 235gaggtgcagc tgttggagtc tgggggaggc
ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt
aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtccagagtg ggtctcacag
atttcgaata ctgctgatcg tacatactac 180gcacactccg tgaagggccg gttcaccatc
tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgctgaggac
accgcggtat attactgtgc gatatatact 300gggcgttggg tgccttttga gtactggggt
cagggaaccc tggtcaccgt ctcgagc 357236357DNAArtificial
SequenceNucleotide 236gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtccagagtg ggtctcacag atttcgaata
ctgctgatcg tacatactac 180gcacactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcggtggg cgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357237357DNAArtificial SequenceNucleotide
237gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcggata ctgctgatcg tacatactac
180gcacactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgctgaggac accgcggtat attactgtgc gatatatact
300gggcgttggg tgccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357238357DNAArtificial SequenceNucleotide 238gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata ctgctgatcg tacatactac 180gcacactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcggtggg cgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357239357DNAArtificial
SequenceNucleotide 239gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ctgctgatcg tacatactac 180gatgactctg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttgga ggccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357240357DNAArtificial SequenceNucleotide
240gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcggata ctgctgatcg tacatactac
180acacactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcggtggg cgccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357241357DNAArtificial SequenceNucleotide 241gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcgaata ctgctgatcg cagatactac 180gcacactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcggtggg cgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357242357DNAArtificial
SequenceNucleotide 242gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag attttgaata
ctgctgatcg tacatactac 180gatcactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcggtggg cgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357243357DNAArtificial SequenceNucleotide
243gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata ctgctgatcg tacatactac
180gatcactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcggtggg cgccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357244357DNAArtificial SequenceNucleotide 244gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata ctgctgatcg tagatactac 180gcacactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcggtggg cgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357245357DNAArtificial
SequenceNucleotide 245gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ctgctgatcg tagatactac 180gatcactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcggtggg cgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357246357DNAArtificial SequenceNucleotide
246gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata ctgctgatcg tacatactac
180gcacactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc ggtatatact
300gggcgttggg tgtcttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357247357DNAArtificial SequenceNucleotide 247gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcgaata ctgctgatcg tacatactac 180gcacactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gctatatact 300gggcgttggg tgtcttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357248357DNAArtificial
SequenceNucleotide 248gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
ctgctgatcg tacatactac 180gcacactccg tgaagggccg gtttaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc ggtatatact 300gggcgttggg tgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357249357DNAArtificial SequenceNucleotide
249gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata ctgctgatcg tacatactac
180gcacactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gctatatact
300gggcgttggg tgccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357250357DNAArtificial SequenceNucleotide 250gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag attgcgaata ctgctgatcg tagatactac 180gcacactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcggtggg cgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357251357DNAArtificial
SequenceNucleotide 251gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcgaata
ctgctgatcg tagatactac 180gcagacgcgg tgaaggggcg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttgt ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357252357DNAArtificial SequenceNucleotide
252gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcgg cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata cgggcgatcg tagatactac
180gcacacgcgg tgaaggggcg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttgt ctactggggt cagggaaccc tggtcaccgt ctcgagc
357253357DNAArtificial SequenceNucleotide 253gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag attgcgaata ctgctgatcg tagatactac 180gcagacgcgg tgaaggggcg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttgt
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357254357DNAArtificial
SequenceNucleotide 254gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag attgcgaata
cgggtgatcg tagatactac 180gcacacgcgg tgaaggggcg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttgt ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357255357DNAArtificial SequenceNucleotide
255gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcgaata ctgctgatcg tagatactac
180gcacacgcgg tgaaggggcg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttgt ctactggggt cagggaaccc tggtcaccgt ctcgagc
357256357DNAArtificial SequenceNucleotide 256gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag attgcgaata cggctgatcg tagatactac 180gcacacgcgg tgaaggggcg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttgt
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357257357DNAArtificial
SequenceNucleotide 257gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag attgtgaata
cgggtgatcg tagatactac 180gcagacgcgg tgaaggggcg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttgt ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357258357DNAArtificial SequenceNucleotide
258gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag attgcgaata cgggtgatcg tagatactac
180gcagacgcgg tgaaggggcg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttgt ctactggggt cagggaaccc tggtcaccgt ctcgagc
357259357DNAArtificial SequenceNucleotide 259gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata ctgctgatcg tacatactac 180gatcactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcggtggg cgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357260357DNAArtificial
SequenceNucleotide 260gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ctgctgatcg tacatactac 180gatcactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttgga ggccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357261357DNAArtificial SequenceNucleotide
261gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcggata ctgctgatcg tacatactac
180gatcactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttgt ctactggggt cagggaaccc tggtcaccgt ctcgagc
357262357DNAArtificial SequenceNucleotide 262gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata ctgctgatcg tacatactac 180tcacactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgctgaggac accgcggtat attactgtgc gatatatact 300gggcgttggg tgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357263357DNAArtificial
SequenceNucleotide 263gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ctgctgatcg tacatactac 180acacactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgctgaggac accgcggtat
attactgtgc gatatatact 300gggcgttggg tgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357264357DNAArtificial SequenceNucleotide
264gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcggata ctgctgatcg tacatactac
180acagacgcgg tgaaggggcg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttgt ctactggggt cagggaaccc tggtcaccgt ctcgagc
357265357DNAArtificial SequenceNucleotide 265gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttttc aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata ctgctgatcg tacatactac 180gcacactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcggtggg cgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357266357DNAArtificial
SequenceNucleotide 266gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttttg aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ctgctgatcg tacatactac 180gcacactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcggtggg cgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357267357DNAArtificial SequenceNucleotide
267gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttttc aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag attgcggata cgggtgatcg tagatactac
180gatgactctg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttgt ctactggggt cagggaaccc tggtcaccgt ctcgagc
357268357DNAArtificial SequenceNucleotide 268gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttttc aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata ctgctgatcg tagatactac 180gatgactctg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttgt
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357269357DNAArtificial
SequenceNucleotide sequences of anti-TNFR1 dAbs 269gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgcctc 60tcctgtgcag cctccggatt
cacctttttc aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata cgggtgatcg tagatactac 180gatcactctg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg aaccttttgt
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357270357DNAArtificial
SequenceNucleotide 270gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttttc aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
cgggtgatcg tagatactac 180gatgacgcgg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttgt ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357271357DNAArtificial SequenceNucleotide
271gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttttc aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag attgcggata ctgctgatcg tagatactac
180gatgactctg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttgt ctactggggt cagggaaccc tggtcaccgt ctcgagc
357272357DNAArtificial SequenceNucleotide 272gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttttc aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag attgcggata cgggtgatcg tagatactac 180gatcactctg tgaagggccg
gttcactatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttgt
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357273357DNAArtificial
SequenceNucleotide 273gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttttc aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag attgcggata
cgggtgatcg tagatactac 180gatgacgcgg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttgt ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357274357DNAArtificial SequenceNucleotide
274gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcggata ctgctgatcg tacatactac
180gcacactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg ggccttttgt ctactggggt cagggaaccc tggtcaccgt ctcgagc
357275357DNAArtificial SequenceNucleotide 275gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata ctgctgatcg tacatactac 180gcacactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg tgccttttgc
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357276357DNAArtificial
SequenceNucleotide 276gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ctgctgatcg tacatactac 180gcacactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg gaccttttca gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357277357DNAArtificial SequenceNucleotide
277gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcggata ctgctgatcg tacatactac
180gcacactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttca gtactggggt cagggaactc tggtcaccgt ctcgagc
357278357DNAArtificial SequenceNucleotide 278gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata ctgctgatcg tacatactac 180gcacactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg cgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357279357DNAArtificial
SequenceNucleotide 279gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ctgctgatcg tacatactac 180gcacactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg cgccttttca gtactggggt cagggaactc
tggtcaccgt ctcgagc 357280357DNAArtificial SequenceNucleotide
280gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcggata ctgctgatcg tacatactac
180gcacactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg tgccttttca gtactggggt cagggcaccc tggtcaccgt ctcgagc
357281357DNAArtificial SequenceNucleotide 281gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata ccggtgatcg tagatactac 180gatcactctg tgaagggccg
gttcactatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcggtggg cgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357282357DNAArtificial
SequenceNucleotide 282gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttttg aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ctgctgatcg tacatactac 180gcacactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgctgaggac accgcggtat
attactgtgc gatatatact 300gggcgttggg tgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357283357DNAArtificial SequenceNucleotide
283gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttttc aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcggata ctgctgatcg tacatactac
180gcacactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgctgaggac accgcggtat attactgtgc gatatatact
300gggcgttggg tgccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357284357DNAArtificial SequenceNucleotide 284gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttttg aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata ctgctgatcg tacatactac 180gatcactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttgga ggccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357285357DNAArtificial
SequenceNucleotide 285gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttttc aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ctgctgatcg tacatactac 180gatcactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttgga ggccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357286357DNAArtificial SequenceNucleotide
286gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttttc aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcggata ctgctgatcg tacatactac
180gatcactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg agccttttgt ctactggggt cagggaaccc tggtcaccgt ctcgagc
357287357DNAArtificial SequenceNucleotide 287gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttttg aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata ctgctgatcg tacatactac 180gatcactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg agccttttgt
ctactggggt cagggaaccc tggtcaccgt ctcgagc 357288357DNAArtificial
SequenceNucleotide 288gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttttg aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ctgctgatcg tacatactac 180tcacactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgctgaggac accgcggtat
attactgtgc gatatatact 300gggcgttggg tgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357289357DNAArtificial SequenceNucleotide
289gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttttc aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcggata ctgctgatcg tacatactac
180tcacactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgctgaggac accgcggtat attactgtgc gatatatact
300gggcgttggg tgccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357290357DNAArtificial SequenceNucleotide 290gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttttc aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata ctgctgatcg tacatactac 180acacactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgctgaggac accgcggtat attactgtgc gatatatact 300gggcgttggg tgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357291357DNAArtificial
SequenceNucleotide 291gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttttg aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ctgctgatcg tacatactac 180acacactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgctgaggac accgcggtat
attactgtgc gatatatact 300gggcgttggg tgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357292357DNAArtificial SequenceNucleotide
292gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttttc aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcggata ctgctgatcg tacatactac
180gcacactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcgttggg cgccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357293357DNAArtificial SequenceNucleotide 293gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttttg aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata ctgctgatcg tacatactac 180gcacactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcgttggg cgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357294357DNAArtificial
SequenceNucleotide 294gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttttc aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ccggtgatcg tagatactac 180gatcactctg tgaagggccg gttcactatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcggtggg cgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357295357DNAArtificial SequenceNucleotide
295gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag attgcggata ctgctgatcg tacatactac
180gcacactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgctgaggac accgcggtat attactgcgc gatatatact
300gggcgttggg tgccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357296357DNAArtificial SequenceNucleotide 296gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttttt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag atttcggata ctgctgatcg tacatactac 180gcacacgcgg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgctgaggac accgcggtat attactgtgc gatatatact 300gggcgttggg tgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357297357DNAArtificial
SequenceNucleotide 297gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttttt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ctgctgatcg tacatactac 180gcacacgcgg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgctgaggac accgcggtat
attactgtgc gatatatact 300gggcgttggg tgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357298357DNAArtificial SequenceNucleotide
298gaggtgcagc tgttggagtc tgggggaggc ttggtgcagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag attgcggata ctgctgatcg tacatactac
180gatcactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgctgaggac accgcggtat attactgtgc gatatatact
300gggcgttggg tgccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357299357DNAArtificial SequenceNucleotide 299gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag attgcggata ctgctgatcg tacatactac 180gatcacgcgg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgctgaggac accgcggtat attactgtgc gatatatact 300gggcgttggg tgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357300357DNAArtificial
SequenceNucleotide 300gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag attgcggata
ctgctgatcg tagatactac 180gcacactccg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcggtggg cgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357301357DNAArtificial SequenceNucleotide
301gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag atttcggata ctgctgatcg tagatactac
180gcacacgcgg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcggtggg cgccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagc
357302357DNAArtificial SequenceNucleotide 302gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag attgcggata ctgctgatcg tagatactac 180gcacacgcgg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcggtggg cgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357303357DNAArtificial
SequenceNucleotide 303gaggtgcagc tgttggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttgtt aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ctgctgatcg tagatactac 180gatcacgcgg tgaagggccg gttcaccatc tcccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcggtggg cgccttttga gtactggggt cagggaaccc
tggtcaccgt ctcgagc 357304357DNAArtificial SequenceNucleotide
304gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttgtt aagtattcga tggggtgggt ccgccaggct
120ccagggaagg gtctagagtg ggtctcacag attgcggata ctgctgatcg tagatactac
180gatcacgcgg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gatatatacg
300ggtcggtggg cgccttttga gtactggggt caggggaccc tggtcaccgt ctcgagc
357305357DNAArtificial SequenceNucleotide 305gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt
cacctttgtt aagtattcga tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg
ggtctcacag attgcggata ctgctgatcg tagatactac 180gatcactccg tgaagggccg
gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
tgccgaggac accgcggtat attactgtgc gatatatacg 300ggtcggtggg cgccttttga
gtactggggt cagggaaccc tggtcaccgt ctcgagc 357306357DNAArtificial
SequenceNucleotide 306gaggtgcagc tgctggagtc tgggggaggc ttggtacagc
ctggggggtc cctgcgtctc 60tcctgtgcag cctccggatt cacctttttc aagtattcga
tggggtgggt ccgccaggct 120ccagggaagg gtctagagtg ggtctcacag atttcggata
ctgctgatcg tagatactac 180gatgacgcgg tgaagggccg gttcaccatc acccgcgaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgcggtat
attactgtgc gatatatacg 300ggtcgttggg agccttttgt ctactggggt cagggaaccc
tggtcaccgt ctcgagc 357307163PRTMouse 307His Gly Glu Gly Thr Phe Thr
Ser Asp Leu Ser Lys Gln Met Glu Glu1 5 10
15 Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn
Gly Gly Pro Ser 20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly
35 40 45 Gly Ser Gly Gly
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 50 55
60 Ser Leu Ser Ala Ser Val Gly Asp Arg
Val Thr Ile Thr Cys Arg Ala65 70 75
80 Ser Gln Trp Ile Gly Ser Gln Leu Ser Trp Tyr Gln Gln Lys
Pro Gly 85 90 95
Lys Ala Pro Lys Leu Leu Ile Met Trp Arg Ser Ser Leu Gln Ser Gly
100 105 110 Val Pro Ser Arg Phe
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 115
120 125 Thr Ile Ser Ser Leu Gln Pro Glu Asp
Phe Ala Thr Tyr Tyr Cys Ala 130 135
140 Gln Gly Ala Ala Leu Pro Arg Thr Phe Gly Gln Gly Thr
Lys Val Glu145 150 155
160 Ile Lys Arg 308489DNAArtificial SequenceNucleotide 308catggtgaag
gaacatttac cagtgacttg tcaaaacaga tggaagagga ggcagtgcgg 60ttatttattg
agtggcttaa gaacggagga ccaagtagcg gggcacctcc gccatcgggt 120ggtggaggcg
gttcaggcgg aggtggcagc ggcggtggcg ggtcggacat ccagatgacc 180cagtctccat
cctccctgtc tgcatctgta ggagaccgtg tcaccatcac ttgccgggca 240agtcagtgga
ttgggtctca gttatcttgg taccagcaga aaccagggaa agcccctaag 300ctcctgatca
tgtggcgttc ctcgttgcaa agtggggtcc catcacgttt cagtggcagt 360ggatctggga
cagatttcac tctcaccatc agcagtctgc aacctgaaga ttttgctacg 420tactactgtg
ctcagggtgc ggcgttgcct aggacgttcg gccaagggac caaggtggaa 480atcaaacgg
489309163PRTHomo
sapiens 309His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu
Glu1 5 10 15 Glu
Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20
25 30 Ser Gly Ala Pro Pro Pro
Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly 35 40
45 Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
Thr Gln Ser Pro Ser 50 55 60
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
Ala65 70 75 80 Ser
Gln Trp Ile Gly Ser Gln Leu Ser Trp Tyr Gln Gln Lys Pro Gly
85 90 95 Lys Ala Pro Lys Leu Leu
Ile Met Trp Arg Ser Ser Leu Gln Ser Gly 100
105 110 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
Gly Thr Asp Phe Thr Leu 115 120
125 Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
Cys Ala 130 135 140
Gln Gly Leu Arg His Pro Lys Thr Phe Gly Gln Gly Thr Lys Val Glu145
150 155 160 Ile Lys
Arg310489DNAArtificial SequenceNucleotide 310catggtgaag gaacatttac
cagtgacttg tcaaaacaga tggaagagga ggcagtgcgg 60ttatttattg agtggcttaa
gaacggagga ccaagtagcg gggcacctcc gccatcgggt 120ggtggaggcg gttcaggcgg
aggtggcagc ggcggtggcg ggtcggacat ccagatgacc 180cagtctccat cctccctgtc
tgcatctgta ggagaccgtg tcaccatcac ttgccgggca 240agtcagtgga ttgggtctca
gttatcttgg taccagcaga aaccagggaa agcccctaag 300ctcctgatca tgtggcgttc
ctcgttgcaa agtggggtcc catcacgttt cagtggcagt 360ggatctggga cagatttcac
tctcaccatc agcagtctgc aacctgaaga ttttgctacg 420tactactgtg ctcagggttt
gaggcatcct aagacgttcg gccaagggac caaggtggaa 480atcaaacgg
489311163PRTHomo sapiens
311His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu1
5 10 15 Glu Ala Val Arg
Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20
25 30 Ser Gly Ala Pro Pro Pro Ser Gly Gly
Gly Gly Gly Ser Gly Gly Gly 35 40
45 Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
Pro Ser 50 55 60
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala65
70 75 80 Ser Gln Trp Ile Gly
Ser Gln Leu Ser Trp Tyr Gln Gln Lys Pro Gly 85
90 95 Lys Ala Pro Lys Leu Leu Ile Met Trp Arg
Ser Ser Leu Gln Ser Gly 100 105
110 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu 115 120 125 Thr
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala 130
135 140 Gln Gly Leu Met Lys Pro
Met Thr Phe Gly Gln Gly Thr Lys Val Glu145 150
155 160 Ile Lys Arg312489DNAArtificial
SequenceNucleotide 312catggtgaag gaacatttac cagtgacttg tcaaaacaga
tggaagagga ggcagtgcgg 60ttatttattg agtggcttaa gaacggagga ccaagtagcg
gggcacctcc gccatcgggt 120ggtggaggcg gttcaggcgg aggtggcagc ggcggtggcg
ggtcggacat ccagatgacc 180cagtctccat cctccctgtc tgcatctgta ggagaccgtg
tcaccatcac ttgccgggca 240agtcagtgga ttgggtctca gttatcttgg taccagcaga
aaccagggaa agcccctaag 300ctcctgatca tgtggcgttc ctcgttgcaa agtggggtcc
catcacgttt cagtggcagt 360ggatctggga cagatttcac tctcaccatc agcagtctgc
aacctgaaga ttttgctacg 420tactactgtg ctcagggtct tatgaagcct atgacgttcg
gccaagggac caaggtggaa 480atcaaacgg
489313163PRTHomo sapiens 313His Gly Glu Gly Thr
Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu1 5
10 15 Glu Ala Val Arg Leu Phe Ile Glu Trp Leu
Lys Asn Gly Gly Pro Ser 20 25
30 Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Gly Ser Gly Gly
Gly 35 40 45 Gly
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 50
55 60 Ser Leu Ser Ala Ser Val
Gly Asp Arg Val Thr Ile Ser Cys Arg Ala65 70
75 80 Ser Gln Trp Ile Gly Ser Gln Leu Ser Trp Tyr
Gln Gln Lys Pro Gly 85 90
95 Glu Ala Pro Lys Leu Leu Ile Met Trp Arg Ser Ser Leu Gln Ser Gly
100 105 110 Val Pro Ser
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 115
120 125 Thr Ile Ser Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Tyr Cys Ala 130 135
140 Gln Gly Ala Ala Leu Pro Arg Thr Phe Gly Gln Gly Thr
Lys Val Glu145 150 155
160 Ile Lys Arg314489DNAArtificial SequenceNucleotide 314catggtgaag
gaacatttac cagtgacttg tcaaaacaga tggaagagga ggcagtgcgg 60ttatttattg
agtggcttaa gaacggagga ccaagtagcg gggcacctcc gccatcgggt 120ggtggaggcg
gttcaggcgg aggtggcagc ggcggtggcg ggtcggacat ccagatgacc 180cagtctccat
cctccctgtc tgcatctgta ggagaccgtg tcaccatctc ttgccgggca 240agtcagtgga
ttgggtctca gttatcttgg taccagcaga aaccagggga agcccctaag 300ctcctgatca
tgtggcgttc ctcgttgcaa agtggggtcc catcacgttt cagtggcagt 360ggatctggga
cagatttcac tctcaccatc agcagtctgc aacctgaaga ttttgctacg 420tactactgtg
ctcagggtgc ggcgttgcct aggacgttcg gccaagggac caaggtggaa 480atcaaacgg
489315163PRTHomo
sapiens 315His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu
Glu1 5 10 15 Glu
Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20
25 30 Ser Gly Ala Pro Pro Pro
Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly 35 40
45 Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
Thr Gln Ser Pro Ser 50 55 60
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
Ala65 70 75 80 Ser
Arg Pro Ile Gly Thr Thr Leu Ser Trp Tyr Gln Gln Lys Pro Gly
85 90 95 Lys Ala Pro Lys Leu Leu
Ile Trp Phe Gly Ser Arg Leu Gln Ser Gly 100
105 110 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
Gly Thr Asp Phe Thr Leu 115 120
125 Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
Cys Ala 130 135 140
Gln Ala Gly Thr His Pro Thr Thr Phe Gly Gln Gly Thr Lys Val Glu145
150 155 160 Ile Lys
Arg316489DNAArtificial SequenceNucleotide 316catggtgaag gaacatttac
cagtgacttg tcaaaacaga tggaagagga ggcagtgcgg 60ttatttattg agtggcttaa
gaacggagga ccaagtagcg gggcacctcc gccatcgggt 120ggtggaggcg gttcaggcgg
aggtggcagc ggcggtggcg ggtcggacat ccagatgacc 180cagtctccat cctccctgtc
tgcatctgta ggagaccgtg tcaccatcac ttgccgggca 240agtcgtccga ttgggacgac
gttaagttgg taccagcaga aaccagggaa agcccctaag 300ctcctgatct ggtttggttc
ccggttgcaa agtggggtcc catcacgttt cagtggcagt 360ggatctggga cagatttcac
tctcaccatc agcagtctgc aacctgaaga ttttgctacg 420tactactgtg cgcaggctgg
gacgcatcct acgacgttcg gccaagggac caaggtggaa 480atcaaacgg
489317163PRTHomo sapiens
317His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu1
5 10 15 Glu Ala Val Arg
Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20
25 30 Ser Gly Ala Pro Pro Pro Ser Gly Gly
Gly Gly Gly Ser Gly Gly Gly 35 40
45 Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
Pro Ser 50 55 60
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala65
70 75 80 Ser Arg Pro Ile Gly
Thr Met Leu Ser Trp Tyr Gln Gln Lys Pro Gly 85
90 95 Lys Ala Pro Lys Leu Leu Ile Leu Phe Gly
Ser Arg Leu Gln Ser Gly 100 105
110 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu 115 120 125 Thr
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala 130
135 140 Gln Ala Gly Thr His Pro
Thr Thr Phe Gly Gln Gly Thr Lys Val Glu145 150
155 160 Ile Lys Arg318489DNAArtificial
SequenceNucleotide 318catggtgaag gaacatttac cagtgacttg tcaaaacaga
tggaagagga ggcagtgcgg 60ttatttattg agtggcttaa gaacggagga ccaagtagcg
gggcacctcc gccatcgggt 120ggtggaggcg gttcaggcgg aggtggcagc ggcggtggcg
ggtcggacat ccagatgacc 180cagtctccat cctccctgtc tgcatctgta ggagaccgtg
tcaccatcac ttgccgggca 240agtcgtccga ttgggacgat gttaagttgg taccagcaga
aaccagggaa agcccctaag 300ctcctgatct tgtttggttc ccggttgcaa agtggggtcc
catcacgttt cagtggcagt 360ggatctggga cagatttcac tctcaccatc agcagtctgc
aacctgaaga ttttgctacg 420tactactgtg cgcaggctgg gacgcatcct acgacgttcg
gccaagggac caaggtggaa 480atcaaacgg
489319163PRTHomo sapiens 319His Gly Glu Gly Thr
Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu1 5
10 15 Glu Ala Val Arg Leu Phe Ile Glu Trp Leu
Lys Asn Gly Gly Pro Ser 20 25
30 Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Gly Ser Gly Gly
Gly 35 40 45 Gly
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 50
55 60 Ser Leu Ser Ala Ser Val
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala65 70
75 80 Ser Arg Pro Ile Gly Thr Met Leu Ser Trp Tyr
Gln Gln Lys Pro Gly 85 90
95 Lys Ala Pro Lys Leu Leu Ile Leu Ala Phe Ser Arg Leu Gln Ser Gly
100 105 110 Val Pro Ser
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 115
120 125 Thr Ile Ser Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Tyr Cys Ala 130 135
140 Gln Ala Gly Thr His Pro Thr Thr Phe Gly Gln Gly Thr
Lys Val Glu145 150 155
160 Ile Lys Arg320489DNAArtificial SequenceNucleotide 320catggtgaag
gaacatttac cagtgacttg tcaaaacaga tggaagagga ggcagtgcgg 60ttatttattg
agtggcttaa gaacggagga ccaagtagcg gggcacctcc gccatcgggt 120ggtggaggcg
gttcaggcgg aggtggcagc ggcggtggcg ggtcggacat ccagatgacc 180cagtctccat
cctccctgtc tgcatctgta ggagaccgtg tcaccatcac ttgccgggca 240agtcgtccga
ttgggacgat gttaagttgg taccagcaga aaccagggaa agcccctaag 300ctcctgatcc
ttgctttttc ccgtttgcaa agtggggtcc catcacgttt cagtggcagt 360ggatctggga
cagatttcac tctcaccatc agcagtctgc aacctgaaga ttttgctacg 420tactactgcg
cgcaggctgg gacgcatcct acgacgttcg gccaagggac caaggtggaa 480atcaaacgg
489321114PRTHomo
sapiens 321Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
Gly1 5 10 15 Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Ser Gln 20
25 30 Leu Ser Trp Tyr Gln Gln
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40
45 Met Trp Arg Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro65 70 75 80 Glu
Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Gly Leu Arg His Pro Lys
85 90 95 Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg Gly Gly Gly Gly 100
105 110 Ser Cys322345DNAArtificial
SequenceNucleotide 322gacatccaga tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga ccgtgtcacc 60atcacttgcc gggcaagtca gtggattggg tctcagttat
cttggtacca gcagaaacca 120gggaaagccc ctaagctcct gatcatgtgg cgttcctcgt
tgcaaagtgg ggtcccatca 180cgtttcagtg gcagtggatc tgggacagat ttcactctca
ccatcagcag tctgcaacct 240gaagattttg ctacgtacta ctgtgctcag ggtttgaggc
atcctaagac gttcggccaa 300gggaccaagg tggaaatcaa acggggtggc ggagggggtt
cctgt 345323115PRTHomo sapiens 323Asp Ile Gln Met Thr
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5
10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
Gln Trp Ile Gly Ser Gln 20 25
30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
Ile 35 40 45 Met
Trp Arg Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50
55 60 Ser Gly Ser Gly Thr Asp
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70
75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Gly
Leu Arg His Pro Lys 85 90
95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110 Pro Ser Cys
115 324345DNAArtificial SequenceNucleotide 324gacatccaga
tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga ccgtgtcacc 60atcacttgcc
gggcaagtca gtggattggg tctcagttat cttggtacca gcagaaacca 120gggaaagccc
ctaagctcct gatcatgtgg cgttcctcgt tgcaaagtgg ggtcccatca 180cgtttcagtg
gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg
ctacgtacta ctgtgctcag ggtttgaggc atcctaagac gttcggccaa 300gggaccaagg
tggaaatcaa acggaccgtc gctgctccat cttgt
345325235PRTMouse 325Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Arg Tyr
20 25 30 Ser Met Gly Trp Leu
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Arg Ile Asp Ser Tyr Gly Arg Gly Thr
Tyr Tyr Glu Asp Pro Val 50 55 60
Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
Tyr65 70 75 80 Leu
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Lys Ile Ser Gln Phe
Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln 100
105 110 Gly Thr Gln Val Thr Val Ser Ser Ala Ser
Thr Ser Gly Pro Ser Asp 115 120
125 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
Gly Asp 130 135 140
Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro Ile Gly Thr Thr Leu145
150 155 160 Ser Trp Tyr Gln Gln
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Trp 165
170 175 Phe Gly Ser Arg Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly Ser 180 185
190 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
Glu 195 200 205 Asp
Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His Pro Thr Thr 210
215 220 Phe Gly Gln Gly Thr Lys
Val Glu Ile Lys Arg225 230 235
326249PRTArtificial SequenceAmino acid plus nucleotide plus myc tag
sequence 326Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
Gly1 5 10 15 Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Arg Tyr 20
25 30 Ser Met Gly Trp Leu Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Arg Ile Asp Ser Tyr Gly Arg Gly Thr Tyr
Tyr Glu Asp Pro Val 50 55 60
Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
Tyr65 70 75 80 Leu
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Lys Ile Ser Gln Phe
Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln 100
105 110 Gly Thr Gln Val Thr Val Ser Ser Ala Ser
Thr Ser Gly Pro Ser Asp 115 120
125 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
Gly Asp 130 135 140
Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro Ile Gly Thr Thr Leu145
150 155 160 Ser Trp Tyr Gln Gln
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Trp 165
170 175 Phe Gly Ser Arg Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly Ser 180 185
190 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
Glu 195 200 205 Asp
Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His Pro Thr Thr 210
215 220 Phe Gly Gln Gly Thr Lys
Val Glu Ile Lys Arg Ala Ala Ala Glu Gln225 230
235 240 Lys Leu Ile Ser Glu Glu Asp Leu Asn
245 327705DNAArtificial SequenceNucleotide
327gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttaat aggtatagta tggggtggct ccgccaggct
120ccagggaagg gtctagagtg ggtctcacgg attgattctt atggtcgtgg tacatactac
180gaagaccccg tgaagggccg gttcagcatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgccgtat attactgtgc gaaaatttct
300cagtttgggt caaatgcgtt tgactactgg ggtcagggaa cccaggtcac cgtctcgagc
360gctagcacca gtggtccatc ggacatccag atgacccagt ctccatcctc cctgtctgca
420tctgtaggag accgtgtcac catcacttgc cgggcaagtc gtccgattgg gacgacgtta
480agttggtacc agcagaaacc agggaaagcc cctaagctcc tgatctggtt tggttcccgg
540ttgcaaagtg gggtcccatc acgtttcagt ggcagtggat ctgggacaga tttcactctc
600accatcagca gtctgcaacc tgaagatttt gctacgtact actgtgcgca ggctgggacg
660catcctacga cgttcggcca agggaccaag gtggaaatca aacgg
705328750DNAArtificial SequenceNucleotide plus myc tag sequence
328gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttaat aggtatagta tggggtggct ccgccaggct
120ccagggaagg gtctagagtg ggtctcacgg attgattctt atggtcgtgg tacatactac
180gaagaccccg tgaagggccg gttcagcatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgccgtat attactgtgc gaaaatttct
300cagtttgggt caaatgcgtt tgactactgg ggtcagggaa cccaggtcac cgtctcgagc
360gctagcacca gtggtccatc ggacatccag atgacccagt ctccatcctc cctgtctgca
420tctgtaggag accgtgtcac catcacttgc cgggcaagtc gtccgattgg gacgacgtta
480agttggtacc agcagaaacc agggaaagcc cctaagctcc tgatctggtt tggttcccgg
540ttgcaaagtg gggtcccatc acgtttcagt ggcagtggat ctgggacaga tttcactctc
600accatcagca gtctgcaacc tgaagatttt gctacgtact actgtgcgca ggctgggacg
660catcctacga cgttcggcca agggaccaag gtggaaatca aacgggcggc cgcagaacaa
720aaactcatct cagaagagga tctgaattaa
750329235PRTHomo sapiens 329Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Arg Tyr
20 25 30 Ser Met Gly
Trp Leu Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Arg Ile Asp Ser Tyr Gly Arg
Gly Thr Tyr Tyr Glu Asp Pro Val 50 55
60 Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn
Thr Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Lys Ile Ser Gln
Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln 100
105 110 Gly Thr Gln Val Thr Val Ser Ser Ala Ser
Thr Ser Gly Pro Ser Asp 115 120
125 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
Gly Asp 130 135 140
Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro Ile Gly Thr Met Leu145
150 155 160 Ser Trp Tyr Gln Gln
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Leu 165
170 175 Phe Gly Ser Arg Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly Ser 180 185
190 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
Glu 195 200 205 Asp
Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His Pro Thr Thr 210
215 220 Phe Gly Gln Gly Thr Lys
Val Glu Ile Lys Arg225 230 235
330249PRTArtificial SequenceAmino acid plus nucleotide plus myc tag
sequence 330Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
Gly1 5 10 15 Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Arg Tyr 20
25 30 Ser Met Gly Trp Leu Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Arg Ile Asp Ser Tyr Gly Arg Gly Thr Tyr
Tyr Glu Asp Pro Val 50 55 60
Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
Tyr65 70 75 80 Leu
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Lys Ile Ser Gln Phe
Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln 100
105 110 Gly Thr Gln Val Thr Val Ser Ser Ala Ser
Thr Ser Gly Pro Ser Asp 115 120
125 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
Gly Asp 130 135 140
Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro Ile Gly Thr Met Leu145
150 155 160 Ser Trp Tyr Gln Gln
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Leu 165
170 175 Phe Gly Ser Arg Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly Ser 180 185
190 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
Glu 195 200 205 Asp
Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His Pro Thr Thr 210
215 220 Phe Gly Gln Gly Thr Lys
Val Glu Ile Lys Arg Ala Ala Ala Glu Gln225 230
235 240 Lys Leu Ile Ser Glu Glu Asp Leu Asn
245 331705DNAArtificial SequenceNucleotide plus myc
tag sequence 331gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc
cctgcgtctc 60tcctgtgcag cctccggatt cacctttaat aggtatagta tggggtggct
ccgccaggct 120ccagggaagg gtctagagtg ggtctcacgg attgattctt atggtcgtgg
tacatactac 180gaagaccccg tgaagggccg gttcagcatc tcccgcgaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgccgtat attactgtgc
gaaaatttct 300cagtttgggt caaatgcgtt tgactactgg ggtcagggaa cccaggtcac
cgtctcgagc 360gctagcacca gtggtccatc ggacatccag atgacccagt ctccatcctc
cctgtctgca 420tctgtaggag accgtgtcac catcacttgc cgggcaagtc gtccgattgg
gacgatgtta 480agttggtacc agcagaaacc agggaaagcc cctaagctcc tgatcttgtt
tggttcccgg 540ttgcaaagtg gggtcccatc acgtttcagt ggcagtggat ctgggacaga
tttcactctc 600accatcagca gtctgcaacc tgaagatttt gctacgtact actgtgcgca
ggctgggacg 660catcctacga cgttcggcca agggaccaag gtggaaatca aacgg
705332750DNAArtificial SequenceNucleotide plus myc tag
sequence 332gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc
cctgcgtctc 60tcctgtgcag cctccggatt cacctttaat aggtatagta tggggtggct
ccgccaggct 120ccagggaagg gtctagagtg ggtctcacgg attgattctt atggtcgtgg
tacatactac 180gaagaccccg tgaagggccg gttcagcatc tcccgcgaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgcg tgccgaggac accgccgtat attactgtgc
gaaaatttct 300cagtttgggt caaatgcgtt tgactactgg ggtcagggaa cccaggtcac
cgtctcgagc 360gctagcacca gtggtccatc ggacatccag atgacccagt ctccatcctc
cctgtctgca 420tctgtaggag accgtgtcac catcacttgc cgggcaagtc gtccgattgg
gacgatgtta 480agttggtacc agcagaaacc agggaaagcc cctaagctcc tgatcttgtt
tggttcccgg 540ttgcaaagtg gggtcccatc acgtttcagt ggcagtggat ctgggacaga
tttcactctc 600accatcagca gtctgcaacc tgaagatttt gctacgtact actgtgcgca
ggctgggacg 660catcctacga cgttcggcca agggaccaag gtggaaatca aacgggcggc
cgcagaacaa 720aaactcatct cagaagagga tctgaattaa
750333235PRTHomo sapiens 333Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Asn Arg Tyr 20 25 30
Ser Met Gly Trp Leu Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Arg Ile Asp
Ser Tyr Gly Arg Gly Thr Tyr Tyr Glu Asp Pro Val 50 55
60 Lys Gly Arg Phe Ser Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95
Ala Lys Ile Ser Gln Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln
100 105 110 Gly Thr Gln Val Thr
Val Ser Ser Ala Ser Thr Ser Gly Pro Ser Asp 115
120 125 Ile Gln Met Thr Gln Ser Pro Ser Ser
Leu Ser Ala Ser Val Gly Asp 130 135
140 Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro Ile Gly
Thr Met Leu145 150 155
160 Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Leu
165 170 175 Ala Phe Ser Arg
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 180
185 190 Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro Glu 195 200
205 Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His Pro
Thr Thr 210 215 220
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg225 230
235 334249PRTArtificial SequenceAmino acid plus nucleotide plus
myc tag sequence 334Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Arg Tyr
20 25 30 Ser Met Gly Trp
Leu Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Arg Ile Asp Ser Tyr Gly Arg Gly
Thr Tyr Tyr Glu Asp Pro Val 50 55 60
Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Lys Ile Ser Gln
Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln 100
105 110 Gly Thr Gln Val Thr Val Ser Ser Ala Ser
Thr Ser Gly Pro Ser Asp 115 120
125 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
Gly Asp 130 135 140
Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro Ile Gly Thr Met Leu145
150 155 160 Ser Trp Tyr Gln Gln
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Leu 165
170 175 Ala Phe Ser Arg Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly Ser 180 185
190 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
Glu 195 200 205 Asp
Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His Pro Thr Thr 210
215 220 Phe Gly Gln Gly Thr Lys
Val Glu Ile Lys Arg Ala Ala Ala Glu Gln225 230
235 240 Lys Leu Ile Ser Glu Glu Asp Leu Asn
245 335705DNAArtificial SequenceNucleotide
335gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttaat aggtatagta tggggtggct ccgccaggct
120ccagggaagg gtctagagtg ggtctcacgg attgattctt atggtcgtgg tacatactac
180gaagaccccg tgaagggccg gttcagcatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgccgtat attactgtgc gaaaatttct
300cagtttgggt caaatgcgtt tgactactgg ggtcagggaa cccaggtcac cgtctcgagc
360gctagcacca gtggtccatc ggacatccag atgacccagt ctccatcctc cctgtctgca
420tctgtaggag accgtgtcac catcacttgc cgggcaagtc gtccgattgg gacgatgtta
480agttggtacc agcagaaacc agggaaagcc cctaagctcc tgatccttgc tttttcccgt
540ttgcaaagtg gggtcccatc acgtttcagt ggcagtggat ctgggacaga tttcactctc
600accatcagca gtctgcaacc tgaagatttt gctacgtact actgcgcgca ggctgggacg
660catcctacga cgttcggcca agggaccaag gtggaaatca aacgg
705336750DNAArtificial SequenceNucleotide plus myc tag sequence
336gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc
60tcctgtgcag cctccggatt cacctttaat aggtatagta tggggtggct ccgccaggct
120ccagggaagg gtctagagtg ggtctcacgg attgattctt atggtcgtgg tacatactac
180gaagaccccg tgaagggccg gttcagcatc tcccgcgaca attccaagaa cacgctgtat
240ctgcaaatga acagcctgcg tgccgaggac accgccgtat attactgtgc gaaaatttct
300cagtttgggt caaatgcgtt tgactactgg ggtcagggaa cccaggtcac cgtctcgagc
360gctagcacca gtggtccatc ggacatccag atgacccagt ctccatcctc cctgtctgca
420tctgtaggag accgtgtcac catcacttgc cgggcaagtc gtccgattgg gacgatgtta
480agttggtacc agcagaaacc agggaaagcc cctaagctcc tgatccttgc tttttcccgt
540ttgcaaagtg gggtcccatc acgtttcagt ggcagtggat ctgggacaga tttcactctc
600accatcagca gtctgcaacc tgaagatttt gctacgtact actgcgcgca ggctgggacg
660catcctacga cgttcggcca agggaccaag gtggaaatca aacgggcggc cgcagaacaa
720aaactcatct cagaagagga tctgaattaa
7503379PRTArtificial SequenceCDR 337Ser Gln Ser Ile Ser Ser Tyr Leu Asn1
5 3388PRTArtificial SequenceCDR 338Tyr Ala
Ala Ser Ser Leu Gln Ser1 5 3399PRTArtificial
SequenceCDR 339Gln Gln Ser Tyr Ser Thr Pro Asn Thr1 5
3409PRTArtificial SequenceCDR 340Ser Arg Pro Ile Gly Thr Thr
Leu Ser1 5 3418PRTArtificial SequenceCDR
341Trp Phe Gly Ser Arg Leu Gln Ser1 5
3429PRTArtificial SequenceCDR 342Ala Gln Ala Gly Thr His Pro Thr Thr1
5 3439PRTArtificial SequenceCDR 343Ser Arg Pro
Ile Gly Thr Met Leu Ser1 5
3448PRTArtificial SequenceCDR 344Leu Phe Gly Ser Arg Leu Gln Ser1
5 3459PRTArtificial SequenceCDR 345Ala Gln Ala Gly Thr
His Pro Thr Thr1 5 3469PRTArtificial
SequenceCDR 346Ser Arg Pro Ile Gly Thr Met Leu Ser1 5
3478PRTArtificial SequenceCDR 347Leu Ala Phe Ser Arg Leu Gln
Ser1 5 3489PRTArtificial SequenceCDR 348Ala
Gln Ala Gly Thr His Pro Thr Thr1 5
3499PRTArtificial SequenceCDR 349Ser Arg Pro Ile Gly Thr Met Leu Ser1
5 3508PRTArtificial SequenceCDR 350Trp Phe Gly
Ser Arg Leu Gln Ser1 5 3519PRTArtificial
SequenceCDR 351Ala Gln Ala Gly Thr His Pro Thr Thr1 5
3529PRTArtificial SequenceCDR 352Ser Arg Pro Ile Gly Thr Met
Leu Ser1 5 3538PRTArtificial SequenceCDR
353Leu Phe Gly Ser Arg Leu Gln Ser1 5
3549PRTArtificial SequenceCDR 354Ala Gln Thr Gly Thr His Pro Thr Thr1
5 3559PRTArtificial SequenceCDR 355Ser Arg Pro
Ile Gly Thr Thr Leu Ser1 5
3568PRTArtificial SequenceCDR 356Leu Trp Phe Ser Arg Leu Gln Ser1
5 3579PRTArtificial SequenceCDR 357Ala Gln Ala Gly Thr
His Pro Thr Thr1 5 3589PRTArtificial
SequenceAlbudAb 358Ser Gln Trp Ile Gly Ser Gln Leu Ser1 5
3598PRTArtificial SequenceCDR 359Met Trp Arg Ser Ser Leu
Gln Ser1 5 3609PRTArtificial SequenceCDR
360Ala Gln Gly Ala Ala Leu Pro Arg Thr1 5
3619PRTArtificial SequenceCDR 361Ser Gln Trp Ile Gly Ser Gln Leu Ser1
5 3628PRTArtificial SequenceCDR 362Met Trp Arg
Ser Ser Leu Gln Ser1 5 3639PRTArtificial
SequenceCDR 363Ala Gln Gly Leu Arg His Pro Lys Thr1 5
3649PRTArtificial SequenceCDR 364Ser Gln Trp Ile Gly Ser Gln
Leu Ser1 5 3658PRTArtificial SequenceCDR
365Met Trp Arg Ser Ser Leu Gln Ser1 5
3669PRTArtificial SequenceCDR 366Ala Gln Gly Leu Met Lys Pro Met Thr1
5 3679PRTArtificial SequenceCDR 367Ser Gln Trp
Ile Gly Ser Gln Leu Ser1 5
3688PRTArtificial SequenceCDR 368Met Trp Arg Ser Ser Leu Gln Ser1
5 3699PRTArtificial SequenceCDR 369Ala Gln Gly Ala Ala
Leu Pro Arg Thr1 5 3709PRTArtificial
SequenceCDR 370Ser Gln Trp Ile Gly Ser Gln Leu Ser1 5
3718PRTArtificial SequenceCDR 371Met Trp Arg Ser Ser Leu Gln
Ser1 5 3729PRTArtificial SequenceCDR 372Ala
Gln Gly Ala Ala Leu Pro Lys Thr1 5
3739PRTArtificial SequenceCDR 373Ser Gln Trp Ile Gly Ser Gln Leu Ser1
5 3748PRTArtificial SequenceCDR 374Met Trp Arg
Ser Ser Leu Gln Ser1 5 3759PRTArtificial
SequenceCDR 375Ala Gln Gly Phe Lys Lys Pro Arg Thr1 5
376165PRTHomo sapiens 376Cys Asp Leu Pro Gln Thr His Ser Leu
Gly Ser Arg Arg Thr Leu Met1 5 10
15 Leu Leu Ala Gln Met Arg Arg Ile Ser Leu Phe Ser Cys Leu
Lys Asp 20 25 30
Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln Phe Gln 35
40 45 Lys Ala Glu Thr Ile
Pro Val Leu His Glu Met Ile Gln Gln Ile Phe 50 55
60 Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala
Ala Trp Asp Glu Thr Leu65 70 75
80 Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp Leu
Glu 85 90 95 Ala
Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr Pro Leu Met Lys
100 105 110 Glu Asp Ser Ile Leu
Ala Val Arg Lys Tyr Phe Gln Arg Ile Thr Leu 115
120 125 Tyr Leu Lys Glu Lys Lys Tyr Ser Pro
Cys Ala Trp Glu Val Val Arg 130 135
140 Ala Glu Ile Met Arg Ser Phe Ser Leu Ser Thr Asn Leu
Gln Glu Ser145 150 155
160 Leu Arg Ser Lys Glu 165 377495DNAArtificial
SequenceInterferon alpha 2b nucleotide 377tgtgatctgc ctcaaaccca
cagcctgggt agcaggagga ccttgatgct cctggcacag 60atgaggagaa tctctctttt
ctcctgcttg aaggacagac atgactttgg atttccccag 120gaggagtttg gcaaccagtt
ccaaaaggct gaaaccatcc ctgtcctcca tgagatgatc 180cagcagatct tcaatctctt
cagcacaaag gactcatctg ctgcttggga tgagaccctc 240ctagacaaat tctacactga
actctaccag cagctgaatg acctggaagc ctgtgtgata 300cagggggtgg gggtgacaga
gactcccctg atgaaggagg actccattct ggctgtgagg 360aaatacttcc aaagaatcac
tctctatctg aaagagaaga aatacagccc ttgtgcctgg 420gaggttgtca gagcagaaat
catgagatct ttttctttgt caacaaactt gcaagaaagt 480ttaagaagta aggaa
49537825DNAArtificial
SequenceIFN2b SOE fragment 5' 378gcccggatcc accggctgtg atctg
2537930DNAArtificial SequenceIFN2b SOE
fragment 3' 379ggaggatgga gactgggtca tctggatgtc
3038030DNAArtificial SequenceVk SOE fragment 5' 380gacatccaga
tgacccagtc tccatcctcc
3038182DNAArtificial SequenceVk SOE fragment 3' to also introduce a myc
tag 381gcgcaagctt ttattaattc agatcctctt ctgagatgag tttttgttct gcggccgccc
60gtttgatttc caccttggtc cc
8238225DNAArtificial SequenceIFN2b SOE fragment 5' 382gcccggatcc
accggctgtg atctg
2538382DNAArtificial SequenceNucleotideVk SOE fragment 3' to also
introduce a myc tag 383gcgcaagctt ttattaattc agatcctctt ctgagatgag
tttttgttct gcggccgccc 60gtttgatttc caccttggtc cc
8238420PRTMouse 384Met Glu Thr Asp Thr Leu Leu
Leu Trp Val Leu Leu Leu Trp Val Pro1 5 10
15 Gly Ser Thr Gly 20
38561DNAArtificial SequenceNucleotide 385atggagaccg acaccctgct gctgtgggtg
ctgctgctgt gggtgcccgg atccaccggg 60c
61386108PRTArtificial
SequenceNucleotide 386Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Ser Gln
20 25 30 Leu Ser Trp Tyr Gln
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40
45 Met Trp Arg Ser Ser Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro65 70 75 80 Glu
Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Gly Leu Arg His Pro Lys
85 90 95 Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Cys 100 105
387324DNAArtificial SequenceNucleotide 387gacatccaga tgacccagtc
tccatcctcc ctgtctgcat ctgtaggaga ccgtgtcacc 60atcacttgcc gggcaagtca
gtggattggg tctcagttat cttggtacca gcagaaacca 120gggaaagccc ctaagctcct
gatcatgtgg cgttcctcgt tgcaaagtgg ggtcccatca 180cgtttcagtg gcagtggatc
tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg ctacgtacta
ctgtgctcag ggtttgaggc atcctaagac gttcggccaa 300gggaccaagg tggaaatcaa
atgc 324388108PRTHomo sapiens
388Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Pro Ala Ser Val Gly1
5 10 15 Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Arg Pro Ile Gly Thr Met 20
25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly
Lys Ala Pro Lys Leu Leu Ile 35 40
45 Leu Ala Phe Ser Arg Leu Gln Ser Gly Val Pro Ser Arg Phe
Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80 Glu Asp Phe Ala Thr
Tyr Tyr Cys Ala Gln Ala Gly Thr His Pro Thr 85
90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
Lys Arg 100 105
389324DNAArtificial Sequencenucleic acid 389gacatccaga tgacccagtc
tccatcctcc ctgcctgcat ctgtaggaga ccgtgtcacc 60atcacttgcc gggcaagtcg
tccgattggg acgatgttaa gttggtacca gcagaaacca 120gggaaagccc ctaagctcct
gatccttgct ttttcccgtt tgcaaagtgg ggtcccatca 180cgtttcagtg gcagtggatc
tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg ctacgtacta
ctgcgcgcag gctgggacgc atcctacgac gttcggccaa 300gggaccaagg tggaaatcaa
acgg 32439062DNAArtificial
SequencePrimer 390gcaacagcgt cgacggacat ccagatgacc cagtctccat cctccctgcc
tgcatctgta 60gg
6239132PRTHomo sapiens 391Gly Val Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr1 5 10
15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
Tyr Tyr Cys 20 25 30
3929PRTHomo sapiens 392Ala Gln Ala Gly Thr His Pro Thr Thr1
5 39332PRTHomo sapiens 393Gly Val Pro Ser Arg Phe Ser
Gly Ser Gly Ser Gly Thr Asp Phe Thr1 5 10
15 Leu Thr Ile Ser Asn Leu Gln Pro Glu Asp Phe Ala
Thr Tyr Tyr Cys 20 25 30
3949PRTHomo sapiens 394Ala Gln Ala Gly Thr His Pro Thr Thr1
5 39532PRTHomo sapiens 395Gly Val Pro Ser Arg Phe
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr1 5
10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val
Ala Thr Tyr Tyr Cys 20 25 30
3969PRTHomo sapiens 396Ala Gln Ala Gly Thr His Pro Thr Thr1
5 39732PRTHomo sapiens 397Gly Val Pro Ser Arg
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr1 5
10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
Phe Ala Thr Tyr Tyr Cys 20 25
30 3989PRTHomo sapiens 398Ala Gln Ala Gly Thr His His Thr Thr1
5 39932PRTHomo sapiens 399Gly Val Pro Ser
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr1 5
10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Tyr Cys 20 25
30 4009PRTHomo sapiens 400Ala Gln Ala Gly Val His Pro Thr
Thr1 5 40196DNAArtificial
SequenceNucleotide 401ggggtcccat cacgtttcag tggcagtgga tctgggacag
atttcactct caccatcagc 60agtctgcaac ctgaagattt tgctacgtac tactgc
9640227DNAArtificial SequenceNucleotide
402gcgcaggctg ggacgcatcc tacgacg
2740396DNAArtificial SequenceNucleotide 403ggggtcccat cacgtttcag
tggcagtgga tctgggacag atttcactct caccatcagc 60aatctgcaac ctgaagattt
tgctacgtac tactgc 9640427DNAArtificial
SequenceNucleotide 404gcgcaggctg ggacgcatcc tacgacg
2740596DNAArtificial SequenceNucleotide 405ggggtcccat
cacgtttcag tggcagtgga tctgggacag atttcactct caccatcagc 60agtctgcaac
ctgaagatgt tgctacgtac tactgt
9640627DNAArtificial SequenceNucleotide 406gcgcaggctg ggacgcatcc tacgacg
2740796DNAArtificial
SequenceNucleotide 407ggggtcccat cacgtttcag tggcagtgga tctgggacag
atttcactct caccatcagc 60agtctgcaac ctgaagattt tgctacgtac tactgt
9640827DNAArtificial SequenceNucleotide
408gcgcaggctg ggacgcatca tacgacg
2740920DNAArtificial SequenceNucleotide 409attttgctac gtactactgt
2041027DNAArtificial
SequenceNucleotide 410gcgcaggctg gggtgcatcc tacgacg
27411108PRTHomo sapiens 411Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro
Ile Gly Thr Met 20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Leu Ala Phe Ser
Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro65 70 75
80 Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His
Pro Thr 85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Trp 100
105 412108PRTHomo sapiens 412Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10
15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Arg Pro
Ile Gly Thr Met 20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Leu Ala Phe Ser
Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro65 70 75
80 Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His
Pro Thr 85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Trp 100
105 413108PRTHomo sapiens 413Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro
Ile Gly Thr Met 20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Leu Ala Phe Ser
Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Asn Leu Gln Pro65 70 75
80 Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His
Pro Thr 85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Trp 100
105 414108PRTHomo sapiens 414Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro
Ile Gly Thr Met 20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Leu Ala Phe Ser
Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro65 70 75
80 Glu Asp Val Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His
Pro Thr 85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Trp 100
105 415108PRTHomo sapiens 415Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro
Ile Gly Thr Met 20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Leu Ala Phe Ser
Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro65 70 75
80 Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His
His Thr 85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Asn Lys Trp 100
105 416108PRTHomo sapiens 416Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro
Ile Gly Thr Met 20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile
35 40 45 Leu Ala Phe Ser
Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro65 70 75
80 Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Thr Gly Thr His
Pro Thr 85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Trp 100
105 417108PRTHomo sapiens 417Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro
Ile Gly Thr Met 20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Leu Ala Phe Ser
Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro65 70 75
80 Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Val His
Pro Thr 85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100
105 418108PRTHomo sapiens 418Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro
Ile Gly Thr Met 20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Leu Ala Phe Ser
Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro65 70 75
80 Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Thr Gly Thr His
Pro Thr 85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Trp 100
105 419108PRTHomo sapiens 419Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10
15 Asp Arg Val Thr Ile Phe Cys Arg Ala Ser Arg Pro
Ile Gly Thr Met 20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Leu Ala Phe Ser
Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro65 70 75
80 Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His
Pro Thr 85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Trp 100
105 420108PRTHomo sapiens 420Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro
Ile Gly Thr Met 20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Leu Ala Phe Ser
Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Asn Leu Gln Pro65 70 75
80 Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His
Pro Thr 85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100
105 421108PRTHomo sapiens 421Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro
Ile Gly Thr Met 20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Leu Ala Phe Ser
Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro65 70 75
80 Glu Asp Val Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His
Pro Thr 85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100
105 422108PRTHomo sapiens 422Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro
Ile Gly Thr Met 20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Leu Ala Phe Ser
Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro65 70 75
80 Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His
His Thr 85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100
105 423108PRTHomo sapiens 423Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro
Ile Gly Thr Met 20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Leu Ala Phe Ser
Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro65 70 75
80 Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His
His Thr 85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Asn Lys Arg 100
105 424324DNAArtificial SequenceNucleotide 424gacatccaga
tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga ccgtgtcacc 60atcacttgcc
gggcaagtcg tccgattggg acgatgttaa gttggtacca gcagaaacca 120gggaaagccc
ctaagctcct gatccttgct ttttcccgtt tgcaaagtgg ggtcccatca 180cgtttcagtg
gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg
ctacgtacta ctgcgcgcag gctgggacgc atcctacgac gttcggccaa 300gggaccaagg
tggaaatcaa atgg
324425324DNAArtificial SequenceNucleotide 425gacatccaga tgacccagtc
tccatcctcc ctgtctgcat ctgtaggaga ccgtgtcacc 60atctcttgcc gggcaagtcg
tccgattggg acgatgttaa gttggtacca gcagaaacca 120gggaaagccc ctaagctcct
gatccttgct ttttcccgtt tgcaaagtgg ggtcccatca 180cgtttcagtg gcagtggatc
tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg ctacgtacta
ctgcgcgcag gctgggacgc atcctacgac gttcggccaa 300gggaccaagg tggaaatcaa
atgg 324426324DNAArtificial
SequenceNucleotide 426gacatccaga tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga ccgtgtcacc 60atcacttgcc gggcaagtcg tccgattggg acgatgttaa
gttggtacca gcagaaacca 120gggaaagccc ctaagctcct gatccttgct ttttcccgtt
tgcaaagtgg ggtcccatca 180cgtttcagtg gcagtggatc tgggacagat ttcactctca
ccatcagcaa tctgcaacct 240gaagattttg ctacgtacta ctgcgcgcag gctgggacgc
atcctacgac gttcggccaa 300gggaccaagg tggaaatcaa atgg
324427324DNAArtificial SequenceNucleotide
427gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga ccgtgtcacc
60atcacttgcc gggcaagtcg tccgattggg acgatgttaa gttggtacca gcagaaacca
120gggaaagccc ctaagctcct gatccttgct ttttcccgtt tgcaaagtgg ggtcccatca
180cgtttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct
240gaagatgttg ctacgtacta ctgtgcgcag gctgggacgc atcctacgac gttcggccaa
300gggaccaagg tggaaatcaa atgg
324428324DNAArtificial SequenceNucleotide 428gacatccaga tgacccagtc
tccatcctcc ctgtctgcat ctgtaggaga ccgtgtcacc 60atcacttgcc gggcaagtcg
tccgattggg acgatgttaa gttggtacca gcagaaacca 120gggaaagccc ctaagctcct
gatccttgct ttttcccgtt tgcaaagtgg ggtcccatca 180cgtttcagtg gcagtggatc
tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg ctacgtacta
ctgtgcgcag gctgggacgc atcatacgac gttcggccaa 300gggaccaagg tggaaaacaa
atgg 324429324DNAArtificial
SequenceNucleotide 429gacatccaga tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga ccgtgtcacc 60atcacttgcc gggcaagtcg tccgattggg acgatgttaa
gttggtacca gcagaaacca 120ggggaagccc ctaagctcct gatccttgct ttttcccgtt
tgcaaagtgg ggtcccatca 180cgtttcagtg gcagtggatc tgggacagat ttcactctca
ccatcagcag tctgcaacct 240gaagattttg ctacgtacta ctgtgcgcag actgggacgc
atcctacgac gttcggccaa 300gggaccaagg tggaaatcaa atgg
324430324DNAArtificial SequenceNucleotide
430gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga ccgtgtcacc
60atcacttgcc gggcaagtcg tccgattggg acgatgttaa gttggtacca gcagaaacca
120gggaaagccc ctaagctcct gatccttgct ttttcccgtt tgcaaagtgg ggtcccatca
180cgtttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct
240gaagattttg ctacgtacta ctgtgcgcag gctggggtgc atcctacgac gttcggccaa
300gggaccaagg tggaaatcaa acgg
324431324DNAArtificial SequenceNucleotide 431gacatccaga tgacccagtc
tccatcctcc ctgtctgcat ctgtaggaga ccgtgtcacc 60atcacttgcc gggcaagtcg
tccgattggg acgatgttaa gttggtacca gcagaaacca 120gggaaagccc ctaagctcct
gatccttgct ttttcccgtt tgcaaagtgg ggtcccatca 180cgtttcagtg gcagtggatc
tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg ctacgtacta
ctgtgcgcag actgggacgc atcctacgac gttcggccaa 300gggaccaagg tggaaatcaa
atgg 324432324DNAArtificial
SequenceNucleotide 432gacatccaga tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga ccgtgtcacc 60atcttttgcc gggcaagtcg tccgattggg acgatgttaa
gttggtacca gcagaaacca 120gggaaagccc ctaagctcct gatccttgct ttttcccgtt
tgcaaagtgg ggtcccatca 180cgtttcagtg gcagtggatc tgggacagat ttcactctca
ccatcagcag tctgcaacct 240gaagattttg ctacgtacta ctgcgcgcag gctgggacgc
atcctacgac gttcggccaa 300gggaccaagg tggaaatcaa atgg
324433324DNAArtificial SequenceNucleotide
433gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga ccgtgtcacc
60atcacttgcc gggcaagtcg tccgattggg acgatgttaa gttggtacca gcagaaacca
120gggaaagccc ctaagctcct gatccttgct ttttcccgtt tgcaaagtgg ggtcccatca
180cgtttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcaa tctgcaacct
240gaagattttg ctacgtacta ctgcgcgcag gctgggacgc atcctacgac gttcggccaa
300gggaccaagg tggaaatcaa acgg
324434324DNAArtificial SequenceNucleotide 434gacatccaga tgacccagtc
tccatcctcc ctgtctgcat ctgtaggaga ccgtgtcacc 60atcacttgcc gggcaagtcg
tccgattggg acgatgttaa gttggtacca gcagaaacca 120gggaaagccc ctaagctcct
gatccttgct ttttcccgtt tgcaaagtgg ggtcccatca 180cgtttcagtg gcagtggatc
tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagatgttg ctacgtacta
ctgtgcgcag gctgggacgc atcctacgac gttcggccaa 300gggaccaagg tggaaatcaa
acgg 324435324DNAArtificial
SequenceNucleotide 435gacatccaga tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga ccgtgtcacc 60atcacttgcc gggcaagtcg tccgattggg acgatgttaa
gttggtacca gcagaaacca 120gggaaagccc ctaagctcct gatccttgct ttttcccgtt
tgcaaagtgg ggtcccatca 180cgtttcagtg gcagtggatc tgggacagat ttcactctca
ccatcagcag tctgcaacct 240gaagattttg ctacgtacta ctgtgcgcag gctgggacgc
atcatacgac gttcggccaa 300gggaccaagg tggaaatcaa acgg
324436324DNAArtificial SequenceNucleotide
436gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga ccgtgtcacc
60atcacttgcc gggcaagtcg tccgattggg acgatgttaa gttggtacca gcagaaacca
120gggaaagccc ctaagctcct gatccttgct ttttcccgtt tgcaaagtgg ggtcccatca
180cgtttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct
240gaagattttg ctacgtacta ctgtgcgcag gctgggacgc atcatacgac gttcggccaa
300gggaccaagg tggaaaacaa acgg
3244376PRTArtificial SequenceLinker 437Thr Val Ala Ala Pro Ser1
5 438108PRTHomo sapiens 438Asp Ile Gln Met Thr Gln Ser Pro Ser
Ser Leu Ser Ala Ser Val Gly1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro Ile Gly
Thr Thr 20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35
40 45 Trp Phe Gly Ser Arg
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro65 70 75
80 Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His Pro
Thr 85 90 95 Thr
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100
105 4396PRTArtificial SequenceLinker 439Gly Gly Gly Gly Ser
Cys1 5 4407PRTArtificial SequenceLinker 440Thr Val Ala
Ala Pro Ser Cys1 5
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