Heparin-Binding Epidermal Growth Factor-like Growth Factor Binding Proteins

• US 20110110956A1
• Filed: 09/26/2008
• Published: 05/12/2011
• Est. Priority Date: 09/26/2007
• Status: Active Grant

• Current Assignee: Amgen Inc., U3 Pharma GmbH (Daiichi Sankyo Company Limited)
• Original Assignee: Amgen Inc., U3 Pharma GmbH (Daiichi Sankyo Company Limited)
• Inventors: Rothe, Mike, Borges, Eric, Prenzel, Norbert, Foord, Orit, Hettmann, Thore, Zwick-Wallasch, Esther
• Granted Patent: US 8,828,382 B2
• Time in Patent Office: Days
• US Class Current: 424/158.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 16/2863 : against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

Provided herein are antigen binding proteins, e.g., human and/or monoclonal antibodies that have affinity for heparin-binding epidermal growth factor-like growth factor (HB-EGF) and neutralize the biological functions of this growth factor.

Claims

1. An isolated antigen binding protein that binds HB-EGF, comprising:

A) one or more light chain complementary determining regions (CDRLs) selected from the group consisting of;

(i) a CDRL1 selected from the group consisting of SEQ ID NOs;

189-217;

(ii) a CDRL2 selected from the group consisting of SEQ ID NOs;

218-233;

(iii) a CDRL3 selected from the group consisting of SEQ ID NOs;

234-274; and

(iv) a CDRL of (i), (ii) or (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than four amino acids;

or

B) one or more heavy chain complementary determining regions (CDRHs) selected from the group consisting of;

(i) a CDRH1 selected from the group consisting of SEQ ID NOs;

275-299;

(ii) a CDRH2 selected from the group consisting of SEQ ID NOs;

300-331;

(iii) a CDRH3 selected from the group consisting of SEQ ID NOs;

332-372; and

(iv) a CDRH of (i), (ii) or (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than four amino acids.

2. The isolated antigen binding protein of claim 1, comprising one or more light chain CDRLs of A), and one or more heavy chain CDRHs of B).

3. The isolated antigen binding protein of claim 1 that comprises at least two CDRLs of A) and at least two CDRHs of B).

4. The isolated antigen binding protein of claim 1 that comprises said CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3.

5. The isolated antigen binding protein of claim 1, wherein

said CDRL of A) is selected from the group consisting of:

(i) a CDRL1 selected from the group consisting of SEQ ID NOs;

189-217;

(ii) a CDRL2 selected from the group consisting of SEQ ID NOs;

218-233;

(iii) a CDRL3 selected from the group consisting of SEQ ID NOs;

234-274; and

(iv) a CDRL of (i), (ii) or (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than two amino acids;

said CDRH of B) is selected from the group consisting of;

(i) a CDRH1 selected from the group consisting of SEQ ID NOs;

275-299;

(ii) a CDRH2 selected from the group consisting of SEQ ID NOs;

300-331;

(iii) a CDRH3 selected from the group consisting of SEQ ID NOs;

332-372; and

(iv) a CDRH of (i), (ii) or (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than two amino acids;

or

C) one or more light chain CDRLs of A) and one or more heavy chain CDRHs of B).

6. The isolated antigen binding protein of claim 1, wherein said antigen binding protein comprises

A) a CDRL selected from the group consisting of

(i) a CDRL1 selected from the group consisting of SEQ ID NOs:

189-217;

(ii) a CDRL2 selected from the group consisting of SEQ ID NOs;

218-233; and

(iii) a CDRL3 selected from the group consisting of SEQ ID NOs;

234-274;

B) a CDRH selected from the group consisting of

(i) a CDRH1 selected from the group consisting of SEQ ID NOs;

275-299;

(ii) a CDRH2 selected from the group consisting of SEQ ID NOs;

300-331; and

(iii) a CDRH3 selected from the group consisting of SEQ ID NOs;

332-372;

or

C) one or more light chain CDRLs of A) and one or more heavy chain CDRHs of B).

7. The isolated antigen binding protein of claim 6, wherein said antigen binding protein comprises

A) a CDRL1 of SEQ ID NOs:

189-217, a CDRL2 of SEQ ID NOs;

218-233, and a CDRL3 of SEQ ID NOs;

234-274, and/or

B) a CDRH1 of SEQ ID NOs;

275-299, a CDRH2 of SEQ ID NOs;

300-331, and a CDRH3 of SEQ ID NOs;

332-372.

8. The isolated antigen binding protein of claim 1, wherein said antigen binding protein comprises a light chain variable region (V_L) having at least 80% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs:

94-141, and/or a heavy chain variable region (V_H) having at least 80% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs;

142-186.

9. The isolated antigen binding protein of claim 8, wherein the V_L has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs:

94-141, and/or the V_H has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs;

142-186.

10. The isolated antigen binding protein of claim 8, wherein the V_L is selected from the group consisting of SEQ ID NOs:

94-141, and/or the V_H is selected from the group consisting of SEQ ID NOs;

142-186.

12. An isolated antigen binding protein that competes for binding with the antigen binding protein of claim 1.

31. An isolated antigen binding protein that competes for binding to human HB-EGF with an antigen binding protein of claim 1.

43. The isolated antigen binding protein of claim 1, wherein said antigen binding protein reduces at least partially HB-EGF-mediated signal transduction.

44. A nucleic acid molecule encoding the antigen binding protein according to claim 1.

50. A method of making the antigen binding protein of claim 1, comprising the step of preparing said antigen binding protein from a host cell that secretes said antigen binding protein.

51. A pharmaceutical composition comprising at least one antigen binding protein of claim 1, and pharmaceutically acceptable carrier, diluents and/or adjuvants.

63. A method for treating or diagnosing a hypoproliferative disease, comprising administering the pharmaceutical composition of claim 51.

65. A method for diagnosing a condition associated with the expression of HB-EGF, comprising contacting a sample with an antigen binding protein of claim 1, and determining the presence of HB-EGF in said sample.

67. A method for preventing or treating a condition associated with the expression of HB-EGF in a patient, comprising administering to a patient in need thereof an effective amount of at least one antigen binding protein of claim 1.

70. A kit comprising a antigen binding protein of claim 1.

11. An isolated antigen binding protein that specifically recognizes at least an IHGE-containing epitope and/or an EGF-like domain of HB-EGF.

13. An isolated antigen binding protein that binds HB-EGF, wherein said antigen binding protein comprises:

A) one or more light chain CDRs (CDRLs) selected from the group consisting of;

(i) a CDRL1 with at least 80% sequence identity to SEQ ID NOs;

189-217;

(ii) a CDRL2 with at least 80% sequence identity to SEQ ID NOs;

218-233; and

(iii) a CDRL3 with at least 80% sequence identity to SEQ ID NOs;

234-274;

B) one or more heavy chain CDRs (CDRHs) selected from the group consisting of;

(i) a CDRH1 with at least 80% sequence identity to SEQ ID NOs;

275-299;

(ii) a CDRH2 with at least 80% sequence identity to SEQ ID NOs;

300-331; and

(iii) a CDRH3 with at least 80% sequence identity to SEQ ID NOs;

332-372;

or

C) one or more light chain CDRLs of A) and one or more heavy chain CDRHs of B).

14. The isolated antigen binding protein of claim 13, wherein said antigen binding protein comprises:

A) one or more CDRLs selected from the group consisting of;

(i) a CDRL1 with at least 90% sequence identity to SEQ ID NOs;

189-217;

(ii) a CDRL2 with at least 90% sequence identity to SEQ ID NOs;

218-233; and

(iii) a CDRL3 with at least 90% sequence identity to SEQ ID NOs;

234-274;

B) one or more CDRHs selected from the group consisting of;

(i) a CDRH1 with at least 90% sequence identity to SEQ ID NOs;

275-299;

(ii) a CDRH2 with at least 90% sequence identity to SEQ ID NOs;

300-331; and

(iii) a CDRH3 with at least 90% sequence identity to SEQ ID NOs;

332-372;

or

C) one or more light chain CDRLs of A) and one or more heavy chain CDRHs of B).

15. An isolated antigen binding protein that binds HB-EGF, the antigen binding protein comprising:

A) a light chain complementary determining region (CDRL) selected from the group consisting of

(i) a CDRL3 selected from the group consisting of SEQ ID NOs;

234-274,

(ii) a CDRL3 that differs in amino acid sequence from the CDRL3 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and

(iii) a CDRL3 amino acid sequence selected from the group consisting of

X₁QX₂X₃X₄X₅PX₆X₇ (SEQ ID NO;

1046), wherein

X₁ is selected from the group consisting of I and M,

X₂ is selected from the group consisting of A, G and S,

X₃ is selected from the group consisting of I and T,

X₄ is selected from the group consisting of H and Q,

X₅ is selected from the group consisting of F, L and W,

7X₆ is selected from the group consisting of C, I, H, L and T,

X₇ is selected from the group consisting of S and T;

QQX₁X₂X₃X₄X₅IT (SEQ ID NO;

1047), wherein

X₁ is selected from the group consisting of I and S,

X₂ is selected from the group consisting of F and Y,

X₃ is selected from the group consisting of F, I, S and Y,

X₄ is selected from the group consisting of A, S and T,

X₅ is selected from the group consisting of P and S;

X₁X₂X₃X₄X₅X₆X₇X₈T (SEQ ID NO;

     1048), wherein

X₁ is selected from the group consisting of L and Q,

X₂ is selected from the group consisting of K, N and Q,

X₃ is selected from the group consisting of A, H, S and Y,

X₄ is selected from the group consisting of H, N and Y,

X₅ is selected from the group consisting of N, S and T,

X₆ is selected from the group consisting of A, F, I, T, V and Y,

X₇ is selected from the group consisting of P and no amino acid,

X₈ is selected from the group consisting of F, L and P;

QX₁X₂DX₃LPX₄X₅ (SEQ ID NO;

1049), wherein

X₁ is selected from the group consisting of H and Q,

X₂ is selected from the group consisting of C and Y,

X₃ is selected from the group consisting of D, I, N, S and Y,

X₄ is selected from the group consisting of F, I and L,

X₅ is selected from the group consisting of A, S and T;

QQX₁X₂X₃X₄PX₅X₆X₇ (SEQ ID NO;

     1050), wherein

X₁ is selected from the group consisting of H and Y,

X₂ is selected from the group consisting of G and N,

X₃ is selected from the group consisting of N and S,

X₄ is selected from the group consisting of S and W,

X₅ is selected from the group consisting of P and no amino acid,

X₆ is selected from the group consisting of R and W,

X₇ is selected from the group consisting of S and T; and

X₁QYX₂X₃X₄X₅X₆X₇F (SEQ ID NO;

     1051), wherein

X₁ is selected from the group consisting of H and Q,

X₂ is selected from the group consisting of F and Y,

X₃ is selected from the group consisting of G, I and S,

X₄ is selected from the group consisting of F, I and T,

X₅ is selected from the group consisting of M, P, S and T,

X₆ is selected from the group consisting of F, L, R and W,

X₇ is selected from the group consisting of S and T; and

/or

B) a heavy chain complementary determining region (CDRH) selected from the group consisting of

(i) a CDRH3 selected from the group consisting of SEQ ID NOs;

332-372,

(ii) a CDRH3 that differs in amino acid sequence from the CDRH3 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and

(iii) a CDRH3 amino acid sequence selected from the group consisting of

X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁DX₁₂ (SEQ ID NO;

1065), wherein

X₁ is selected from the group consisting of E and S,

X₂ is selected from the group consisting of D, G and no amino acid,

X₃ is selected from the group consisting of D, N and no amino acid,

X₄ is selected from the group consisting of G and no amino acid,

X₅ is selected from the group consisting of G and no amino acid,

X₆ is selected from the group consisting of W, Y and no amino acid,

X₇ is selected from the group consisting of I, N and Y,

X₈ is selected from the group consisting of A and Y,

X₉ is selected from the group consisting of G, V and Y,

X₁₀ is selected from the group consisting of A, F and G,

X₁₁ is selected from the group consisting of F, L and M,

X₁₂ is selected from the group consisting of V and Y;

QX₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁YX₁₂X₁₃X₁₄DX₁₅ (SEQ ID NO;

1066), wherein

X₁ is selected from the group consisting of G and no amino acid,

X₂ is selected from the group consisting of K, L and Y,

X₃ is selected from the group consisting of A, G and S,

X₄ is selected from the group consisting of S, V and Y,

X₅ is selected from the group consisting of A and G,

X₆ is selected from the group consisting of G and no amino acid,

X₇ is selected from the group consisting of T and no amino acid,

X₈ is selected from the group consisting of S and no amino acid,

X₉ is selected from the group consisting of Y and no amino acid,

X₁₀ is selected from the group consisting of W and Y,

X₁₁ is selected from the group consisting of G, S and Y,

X₁₂ is selected from the group consisting of F and Y,

X₁₃ is selected from the group consisting of G and no amino acid,

X₁₄ is selected from the group consisting of M and no amino acid,

X₁₅ is selected from the group consisting of V and Y;

X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃X₁₄ (SEQ ID NO;

1067), wherein

X₁ is selected from the group consisting of D, G, L, S and no amino acid,

X₂ is selected from the group consisting of G, H, W, Y and no amino acid,

X₃ is selected from the group consisting of A, F, W, Y and no amino acid,

X₄ is selected from the group consisting of D, G, Q, T and no amino acid,

X₅ is selected from the group consisting of G, I, Q, S and no amino acid,

X₆ is selected from the group consisting of A, D, N, Q, S and no amino acid,

X₇ is selected from the group consisting of G, Y and no amino acid,

X₈ is selected from the group consisting of D, Y and no amino acid,

X₉ is selected from the group consisting of Y and no amino acid,

X₁₀ is selected from the group consisting of A, E, N and Y,

X₁₁ is selected from the group consisting of G, P, T, V and Y,

X₁₂ is selected from the group consisting of F and I,

X₁₃ is selected from the group consisting of D and Q,

X₁₄ is selected from the group consisting of C, H, V and Y;

X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃X₁₄X₁₅X₁₆X₁₇DX₁₈ (SEQ ID NO;

     1068), wherein

X₁ is selected from the group consisting of E, D and no amino acid,

X₂ is selected from the group consisting of G, R and no amino acid,

X₃ is selected from the group consisting of I, V, Y and no amino acid,

X₄ is selected from the group consisting of A, G, L and N,

X₅ is selected from the group consisting of A, G, V and W,

X₆ is selected from the group consisting of A, N, R and T,

X₇ is selected from the group consisting of G, N, P and no amino acid,

X₈ is selected from the group consisting of G, T and no amino acid,

X₉ is selected from the group consisting of A and no amino acid,

X₁₀ is selected from the group consisting of D, E and no amino acid,

X₁₁ is selected from the group consisting of S, Y and no amino acid,

X₁₂ is selected from the group consisting of G, Y and no amino acid,

X₁₃ is selected from the group consisting of N, Y and no amino acid,

X₁₄ is selected from the group consisting of Y and no amino acid,

X₁₅ is selected from the group consisting of D, Y and no amino acid,

X₁₆ is selected from the group consisting of A, G and no amino acid,

X₁₇ is selected from the group consisting of F and M,

X₁₈ is selected from the group consisting of I, V and Y;

X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃X₁₄X₁₅X₁₆X₁₇X₁₈X₁₉X₂₀X₂₁X₂₂X₂₃ (SEQ ID NO;

     1069), wherein

X₁ is selected from the group consisting of A, D, G, S and T,

X₂ is selected from the group consisting of A, E, G, L, N, R, Y and no amino acid,

X₃ is selected from the group consisting of A, G, L, N, R, T, Y and no amino acid,

X₄ is selected from the group consisting of D, G, R, S, V, Y and no amino acid,

X₅ is selected from the group consisting of A, G, I, S, V, Y and no amino acid,

X₆ is selected from the group consisting of F, G, L, R, V and no amino acid,

X₇ is selected from the group consisting of L, T, Y and no amino acid,

X₈ is selected from the group consisting of Y and no amino acid,

X₉ is selected from the group consisting of Y and no amino acid,

X₁₀ is selected from the group consisting of D and no amino acid,

X₁₁ is selected from the group consisting of S and no amino acid,

X₁₂ is selected from the group consisting of S and no amino acid,

X₁₃ is selected from the group consisting of G and no amino acid,

X₁₄ is selected from the group consisting of D, L, M, S, Y and no amino acid,

X₁₅ is selected from the group consisting of H, I, P, V, W and no amino acid,

X₁₆ is selected from the group consisting of F, G, L, R, S, Y and no amino acid,

X₁₇ is selected from the group consisting of D, F, V, W, Y and no amino acid,

X₁₈ is selected from the group consisting of C, F, L, P, S and Y,

X₁₉ is selected from the group consisting of D, F, G and Y,

X₂₀ is selected from the group consisting of A, C, G, P, R, V and Y,

X₂₁ is selected from the group consisting of F, L, M, S and no amino acid,

X₂₂ is selected from the group consisting of A, D and no amino acid,

X₂₃ is selected from the group consisting of I, L, V, Y and no amino acid;

X₁YSSGWX₂X₃YGX₄X₅DX₆ (SEQ ID NO;

     1070), wherein

X₁ is selected from the group consisting of M and V,

X₂ is selected from the group consisting of S and no amino acid,

X₃ is selected from the group consisting of F and no amino acid,

X₄ is selected from the group consisting of V and no amino acid,

X₅ is selected from the group consisting of F and M,

X₆ is selected from the group consisting of V and Y; and

RX₁X₂X₃PFX₄Y (SEQ ID NO;

1071), wherein

X₁ is selected from the group consisting of G, H, L, N and R,

X₂ is selected from the group consisting of E, T and W,

X₃ is selected from the group consisting of L, N, T and V,

X₄ is selected from the group consisting of D and E.

16. The isolated antigen binding protein of claim 15, said antigen binding protein further comprising:

A) a CDRL selected from the group consisting of;

(i) a CDRL1 selected from the group consisting of SEQ ID NOs;

189-217;

(ii) a CDRL1 that differs in amino acid sequence from the CDRL1 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids;

(iii) a CDRL1 amino acid sequence selected from the group consisting of

X₁SSQSLX₂X₃SDGX₄TYLX₅ (SEQ ID NO;

1035), wherein

X₁ is selected from the group consisting of K and R,

X₂ is selected from the group consisting of L and V,

X₃ is selected from the group consisting of H and Y,

X₄ is selected from the group consisting of K and N,

X₅ is selected from the group consisting of N, S and Y;

RASQX₁SX₂YLN (SEQ ID NO;

     1036), wherein

X₁ is selected from the group consisting of R, S and T,

X₂ is selected from the group consisting of R and S;

RASQX₁IX₂X₃X₄LX₅ (SEQ ID NO;

     1037), wherein

X₁ is selected from the group consisting of D, G, S and T,

X₂ is selected from the group consisting of A, R and S,

X₃ is selected from the group consisting of H, I, N, R, S and T,

X₄ is selected from the group consisting of D, W and Y,

X₅ is selected from the group consisting of A, G and N;

QASQDIX₁X₂X₃LN (SEQ ID NO;

     1038), wherein

X₁ is selected from the group consisting of S and T,

X₂ is selected from the group consisting of D and N,

X₃ is selected from the group consisting of S and Y;

RASQX₁VX₂X₃X₄X₅LA (SEQ ID NO;

1039), wherein

X₁ is selected from the group consisting of S and T,

X₂ is selected from the group consisting of I and S,

X₃ is selected from the group consisting of R and S,

X₄ is selected from the group consisting of S, N and no amino acid,

X₅ is selected from the group consisting of Y and no amino acid; and

KSSQX₁X₂LX₃X₄SNNKNYLX₅ (SEQ ID NO;

1040), wherein

X₁ is selected from the group consisting of N and S,

X₂ is selected from the group consisting of I and V,

X₃ is selected from the group consisting of D and Y,

X₄ is selected from the group consisting of N, R and S,

X₅ is selected from the group consisting of A and V;

(iv) a CDRL2 selected from the group consisting of SEQ ID NOs;

218-233;

(v) a CDRL2 that differs in amino acid sequence from the CDRL2 of (iv) by an amino acid addition, deletion or substitution of not more than two amino acids; and

(vi) a CDRL2 amino acid sequence selected from the group consisting of

X₁X₂SNX₃X₄S (SEQ ID NO;

1041), wherein

X₁ is selected from the group consisting of E and K,

X₂ is selected from the group consisting of I and V,

X₃ is selected from the group consisting of R and W,

X₄ is selected from the group consisting of D and F;

X₁X₂SX₃LQS (SEQ ID NO;

     1042), wherein

X₁ is selected from the group consisting of A and T,

X₂ is selected from the group consisting of A, E and V,

X₃ is selected from the group consisting of S and T;

X₁ASX₂LQS (SEQ ID NO;

1043), wherein

X₁ is selected from the group consisting of A and V,

X₂ is selected from the group consisting of S and T;

DASX₁LET (SEQ ID NO;

1044), wherein

X₁ is selected from the group consisting of I and N;

GASSRAT (SEQ ID NO;

223); and

WASX₁RES (SEQ ID NO;

     1045), wherein

X₁ is selected from the group consisting of A and T;

or

B) a CDRH selected from the group consisting of;

(i) a CDRH1 selected from the group consisting of SEQ ID NOs;

275-299;

(ii) a CDRH1 that differs in amino acid sequence from the CDRH1 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids;

(iii) a CDRH1 amino acid sequence selected from the group consisting of GYTX₁TX₂X₃X₄X₅X₆ (SEQ ID NO;

     1052), wherein

X₁ is selected from the group consisting of F and L,

X₂ is selected from the group consisting of E, G and S,

X₃ is selected from the group consisting of H, L and Y,

X₄ is selected from the group consisting of G, S and Y,

X₅ is selected from the group consisting of I and M,

X₆ is selected from the group consisting of H and S;

GYX₁FTSYWIG (SEQ ID NO;

     1053), wherein

X₁ is selected from the group consisting of R and S;

GFTFX₁SX₂X₃MH (SEQ ID NO;

     1054), wherein

X₁ is selected from the group consisting of R and S,

X₂ is selected from the group consisting of H and Y,

X₃ is selected from the group consisting of D and G;

GFX₁FSX₂YX₃MX₄ (SEQ ID NO;

1055), wherein

X₁ is selected from the group consisting of P and T,

X₂ is selected from the group consisting of A, R and S,

X₃ is selected from the group consisting of A and S,

X₄ is selected from the group consisting of N and S;

GX₁SX₂SX₃X₄X₅X₆X₇WX₈ (SEQ ID NO;

1056), wherein

X₁ is selected from the group consisting of D and G,

X₂ is selected from the group consisting of F, I and V,

X₃ is selected from the group consisting of R, S and no amino acid,

X₄ is selected from the group consisting of G, Y and no amino acid,

X₅ is selected from the group consisting of D, G, S and no amino acid,

X₆ is selected from the group consisting of A, S and Y,

X₇ is selected from the group consisting of A and Y,

X₈ is selected from the group consisting of N and S;

GFSLSNARMGVS (SEQ ID NO;

279); and

GFSLX₁TGGVGVG (SEQ ID NO;

     1057), wherein

X₁ is selected from the group consisting of S and N;

(iv) a CDRH2 selected from the group consisting of SEQ ID NOs;

300-331;

(v) a CDRH2 that differs in amino acid sequence from the CDRH2 of (iv) by an amino acid addition, deletion or substitution of not more than two amino acids; and

(vi) a CDRH2 amino acid sequence selected from the group consisting of

X₁X₂X₃X₄X₅X₆GX₇TX₈X₉X₁₀QKX₁₁X₁₂ (SEQ ID NO;

1058), wherein

X₁ is selected from the group consisting of S and W,

X₂ is selected from the group consisting of F and I,

X₃ is selected from the group consisting of D, N and S,

X₄ is selected from the group consisting of A and P,

X₅ is selected from the group consisting of E, N and S,

X₆ is selected from the group consisting of D, N and S,

X₇ is selected from the group consisting of E, G and N,

X₈ is selected from the group consisting of I and N,

X₉ is selected from the group consisting of C, H and Y,

X₁₀ is selected from the group consisting of A and T,

X₁₁ is selected from the group consisting of F and L,

X₁₂ is selected from the group consisting of D and G;

IIYPX₁DSDX₂RYSPSFQG (SEQ ID NO;

     1059), wherein

X₁ is selected from the group consisting of D and G,

X₂ is selected from the group consisting of A, I and T;

X₁IX₂X₃DGSX₄X₅X₆YX₇DSVX₈G (SEQ ID NO;

1060), wherein

X₁ is selected from the group consisting of F and V,

X₂ is selected from the group consisting of S and W,

X₃ is selected from the group consisting of D, S and Y,

X₄ is selected from the group consisting of I, N and T,

X₅ is selected from the group consisting of K and Q,

X₆ is selected from the group consisting of N, R and Y,

X₇ is selected from the group consisting of A, T and V,

X₈ is selected from the group consisting of K and R;

X₁ISX₂SX₃X₄X₅X₆YYADSVKG (SEQ ID NO;

1061), wherein

X₁ is selected from the group consisting of A, H and Y,

X₂ is selected from the group consisting of G, R and S,

X₃ is selected from the group consisting of G and S,

X₄ is selected from the group consisting of G, R and S,

X₅ is selected from the group consisting of S, T and Y,

X₆ is selected from the group consisting of I and T;

X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁YX₁₂X₁₃SX₁₄KS (SEQ ID NO;

     1062), wherein

X₁ is selected from the group consisting of E, R and Y,

X₂ is selected from the group consisting of I and T,

X₃ is selected from the group consisting of H, N and Y,

X₄ is selected from the group consisting of C, H, S, T and Y,

X₅ is selected from the group consisting of S and R,

X₆ is selected from the group consisting of G and S,

X₇ is selected from the group consisting of G, K, S and T,

X₈ is selected from the group consisting of T and W,

X₉ is selected from the group consisting of N and Y,

X₁₀ is selected from the group consisting of N and no amino acid,

X₁₁ is selected from the group consisting of D and no amino acid,

X₁₂ is selected from the group consisting of A and N,

X₁₃ is selected from the group consisting of P and V,

X₁₄ is selected from the group consisting of L and V;

X₁IFSNDEKSYSTSLKS (SEQ ID NO;

1063), wherein

X₁ is selected from the group consisting of H and LI; and

LIYWNX₁X₂KRYSPSLX₃S (SEQ ID NO;

     1064), wherein

X₁ is selected from the group consisting of D and V,

X₂ is selected from the group consisting of D and E,

X₃ is selected from the group consisting of K and R.

17-18. -18. (canceled)

20-30. -30. (canceled)

32-42. -42. (canceled)

45-49. -49. (canceled)

52-62. -62. (canceled)

64. (canceled)

66. (canceled)

68-69. -69. (canceled)

71-74. -74. (canceled)