HUMAN C-FMS ANTIGEN BINDING PROTEINS

• US 20090155164A1
• Filed: 08/20/2008
• Published: 06/18/2009
• Est. Priority Date: 08/21/2007
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Foster, Stephen, Cerretti, Douglas Pat, Brasel, Kenneth Allan, Smothers, James F., Mehlin, Christopher, Sun, Jilin
• Granted Patent: US 8,182,813 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 3/10 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/7153 for colony-stimulating factors [CSF]
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• 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 2317/41 : Glycosylation, sialylation, or fucosylation
• 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

Antigen binding proteins that bind to human c-fms protein are provided. Nucleic acids encoding the antigen binding protein, vectors, and cells encoding the same are also provided. The antigen binding proteins can inhibit binding of c-fms to CSF-1, reduce monocyte migration into tumors, and reduce the accumulation of tumor-associated macrophages.

Claims

1. An isolated human antigen binding protein that specifically binds to a human c-fms polypeptide.

2. The isolated human antigen binding protein of claim 1, wherein said human c-fms has the sequence consisting essentially of SEQ ID NO:

1.

3. The isolated human antigen binding protein of claim 1, wherein said human c-fms has the sequence consisting of SEQ ID NO:

1.

4. The isolated human antigen binding protein of claim 1, wherein the binding affinity between said isolated human antigen binding protein and the human c-fms has a K_D of less than 550 picomolar.

5. The isolated human antigen binding protein of claim 1, wherein the binding between said isolated human antigen binding protein and a mutant human c-fms is less than 50% of the binding between said isolated antigen binding protein and the human c-fms of SEQ ID NO:

1.

6. The isolated human antigen binding protein of claim 5, wherein the mutant human c-fms comprises at least one mutation of a residue at a position selected from the group consisting of 102, 144, 146, 174 and 226 as shown in SEQ ID NO:

1.

7. The isolated human antigen binding protein of claim 5, wherein said mutant human c-fms comprises at least one mutation selected from the group consisting of E29R, Q121R, T152R, and K185E.

8. The isolated human antigen binding protein of claim 5, wherein said mutant human c-fms comprises at least one mutation selected from the group consisting of E29R, Q121R, S172R, G274R, and Y276R.

9. The isolated human antigen binding protein of claim 5, wherein said mutant human c-fms comprises at least one mutation selected from the group consisting of R106E, H151R, T152R, Y154R, S155R, W159R, Q171R, S172R, Q173R, G183R, R184E, K185E, E218R, A220R, S228R, H239R, N240R, K259E, G274R, N275R, Y276R, S277R, and N282R.

10. The isolated human antigen binding protein of claim 5, wherein said mutant human c-fms comprises at least one mutation selected from the group consisting of K102E, R144E, R146E, D174R, and A226R.

21. The isolated antigen binding protein of claim 1 that specifically binds to an epitope containing the c-fms subdomains Ig-like 1-1 and Ig-like 1-2 of said human c-fms.

31. An isolated antigen binding protein that competes for binding to the extracellular portion of human c-fms with an antigen binding protein of claim 1.

32. The isolated antigen binding protein of claim 1, wherein said antigen binding protein is a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, or an antibody fragment thereof.

33. The isolated antigen binding protein of claim 32, wherein said antibody fragment is a Fab fragment, a Fab′

fragment, a F(ab′

)₂ fragment, a Fv fragment, a diabody, or a single chain antibody molecule.

34. The isolated antigen binding protein of claim 32, wherein said antigen binding protein is a human antibody.

35. The isolated antigen binding protein of claim 32, wherein said antigen binding protein is a monoclonal antibody.

36. The isolated antigen binding protein of claim 32, wherein said antigen binding protein is of the IgG1-, IgG2- IgG3- or IgG4-type.

37. The isolated antigen binding protein of claim 36, wherein said antigen binding protein is of the IgG1- or the IgG2-type.

38. The isolated antigen binding protein of claim 1, wherein said antigen binding protein is coupled to a labeling group.

39. The isolated antigen binding protein of claim 1, wherein said antigen binding protein inhibits binding of CSF-1 to the extracellular portion of human c-fms.

40. The isolated antigen binding protein of claim 1, wherein said antigen binding protein reduces monocyte chemotaxis when administered to a patient.

41. The isolated antigen binding protein of claim 1, wherein said antigen binding protein inhibits monocyte migration into tumors when administered to a patient.

42. The isolated antigen binding protein of claim 1, wherein said antigen binding protein inhibits accumulation of tumor associated macrophage in a tumor when administered to a patient.

43. A nucleic acid molecule encoding the antigen binding protein of claim 1.

44. The nucleic acid molecule according to claim 43, wherein said nucleic acid molecule is operably linked to a control sequence.

45. A vector comprising a nucleic acid molecule according to claim 43.

46. A vector comprising a nucleic acid molecule according to claim 44.

47. A host cell comprising the nucleic acid molecule according to claim 44.

48. A host cell comprising the vector according to claim 45.

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

50. A pharmaceutical composition comprising at least one antigen binding protein according to claim 1, and pharmaceutically acceptable excipient.

51. The pharmaceutical composition of claim 50, further comprises an additional active agent.

52. The pharmaceutical composition of claim 51, wherein said additional active agent is selected from the group consisting of a radioisotope, radionuclide, a toxin, or a therapeutic and a chemotherapeutic group.

53. A method for treating or preventing a condition associated with c-fms in a patient, comprising administering to a patient in thereof an effective amount of at least one isolated antigen binding protein according to claim 1.

54. The method of claim 53, wherein the condition is cancer.

55. The method of claim 54, wherein the cancer is selected from the group consisting of breast cancer, prostate cancer, endometrial adenocarcinoma, leukemia, lymphoma, astrocytic cancer, endometrial cancer, cervical cancer, bladder cancer, renal cancer, and ovarian cancer.

56. The method of claim 53, wherein the condition is a bone disease.

57. The method of claim 53, wherein the condition is an inflammatory disease.

58. A method of inhibiting binding of CSF-1 to the extracellular portion of human c-fms in a patient comprising administering an effective amount of at least one antigen binding protein according to claim 1.

59. A method of inhibiting autophosphorylation of human c-fms in a patient comprising administering an effective amount of at least one antigen binding protein according to claim 1.

60. A method of reducing monocyte chemotaxis in a patient comprising administering an effective amount of at least one antigen binding protein according to claim 1.

61. A method of inhibiting monocyte migration into tumors in a patient comprising administering an effective amount of at least one antigen binding protein according to claim 1.

62. A method of inhibiting accumulation of tumor associated macrophage in a tumor in a patient comprising administering an effective amount of at least one antigen binding protein according to claim 1.

11. An isolated antigen binding protein that binds human c-fms comprising:

A) 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 NO;

136-147;

(ii) a CDRH2 selected from the group consisting of SEQ ID NO;

148-164;

(iii) a CDRH3 selected from the group consisting of SEQ ID NO;

165-190; and

(iv) a CDRH of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 4 amino acids;

B) 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 NO;

191-210;

(ii) a CDRL2 selected from the group consisting of SEQ ID NO;

211-224;

(iii) a CDRL3 selected from the group consisting of SEQ ID NO;

225-246; and

(iv) a CDRL of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 4 amino acids;

or

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

12. The isolated antigen-binding protein of claim 11 that comprises at least one CDRH of A) and at least one CDRL of B).

13. The isolated antigen-binding protein of claim 11 that comprises at least two CDRH of A) and at least two CDRL of B).

14. The isolated antigen-binding protein of claim 11 that comprises said CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3.

15. The isolated antigen binding protein of claim 11, wherein said CDRH of A) is selected from the group consisting of:

(i) a CDRH1 selected from the group consisting of SEQ ID NO;

136-147;

(ii) a CDRH2 selected from the group consisting of SEQ ID NO;

148-164;

(iii) a CDRH3 selected from the group consisting of SEQ ID NO;

165-190; and

(iv) a CDRH of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 2 amino acids;

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

(i) a CDRL1 selected from the group consisting of SEQ ID NO;

191-210;

(ii) a CDRL2 selected from the group consisting of SEQ ID NO;

211-224;

(iii) a CDRL3 selected from the group consisting of SEQ ID NO;

225-246; and

(iv) a CDRL of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 2 amino acids;

or

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

16. The isolated antigen binding protein of claim 11, wherein said antigen binding protein comprises:

A) a CDRH selected from the group consisting of

(i) a CDRH1 selected from the group consisting of SEQ ID NO;

136-147;

(ii) a CDRH2 selected from the group consisting of SEQ ID NO;

148-164; and

(iii) a CDRH3 selected from the group consisting of SEQ ID NO;

165-190;

B) a CDRL selected from the group consisting of

(i) a CDRL1 selected from the group consisting of SEQ ID NO;

191-210;

(ii) a CDRL2 selected from the group consisting of SEQ ID NO;

211-224; and

(iii) a CDRL3 selected from the group consisting of SEQ ID NO;

225-246;

or

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

17. The isolated antigen binding protein of claim 16, wherein said antigen binding protein comprises:

A) a CDRH1 of SEQ ID NO;

136-147, a CDRH2 of SEQ ID NO;

148-164, and a CDRH3 of SEQ ID NO;

165-190, and

B) a CDRL1 of SEQ ID NO;

191-210, a CDRL2 of SEQ ID NO;

211-224, and a CDRL3 of SEQ ID NO;

225-246.

18. The isolated antigen binding protein of claim 11, wherein said antigen binding protein comprises a heavy chain variable region (VH) having at least 80% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO:

70-101, and/or a light chain variable region (VL) having at least 80% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO;

102-135.

19. The isolated antigen binding protein of claim 18, wherein the VH has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO:

70-101, and/or the VL has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO;

102-135.

20. The isolated antigen binding protein of claim 18, wherein the VH is selected from the group consisting of SEQ ID NO:

70-101, and/or the VL is selected from the group consisting of SEQ ID NO;

102-135.

22. An isolated antigen binding protein that binds human c-fms, wherein said antigen binding protein comprises:

A) 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 NO;

136-147;

(ii) a CDRH2 with at least 80% sequence identity to SEQ ID NO;

148-164; and

(iii) a CDRH3 with at least 80% sequence identity to SEQ ID NO;

165-190;

B) 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 NO;

191-210;

(ii) a CDRL2 with at least 80% sequence identity to SEQ ID NO;

211-224; and

(iii) a CDRL3 with at least 80% sequence identity to SEQ ID NO;

225-246;

or

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

23. The isolated antigen binding protein of claim 22, wherein said antigen binding protein comprises:

A) one or more CDRHs selected from the group consisting of

(i) a CDRH1 with at least 90% sequence identity to SEQ ID NO;

136-147;

(ii) a CDRH2 with at least 90% sequence identity to SEQ ID NO;

148-164; and

(iii) a CDRH3 with at least 90% sequence identity to SEQ ID NO;

165-190;

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

(i) a CDRL1 with at least 90% sequence identity to SEQ ID NO;

191-210;

(ii) a CDRL2 with at least 90% sequence identity to SEQ ID NO;

211-224; and

(iii) a CDRL3 with at least 90% sequence identity to SEQ ID NO;

225-246;

or

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

24. An isolated antigen binding protein that binds human c-fms, wherein said antigen binding protein comprises:

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

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

165-190,

(2) 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

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

(a) X₁X₂X₃X₄X₅FGEX₆X₇X₈X₉FDY (SEQ ID NO;

309), wherein

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

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

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

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

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

X₆ is selected from the group consisting of V and L,

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

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

X₉ is selected from the group consisting of F and L;

25. An isolated antigen binding protein that binds human c-fms, wherein said antigen binding protein is selected from the group consisting of:

(A) an isolated antigen binding protein comprising a CDRH3 of claim 24 (A)(3)(a), a CDRL3 of claim 24 (B)(3)(a), and a CDR selected from the group consisting of;

(1) a CDRH1 selected from the group consisting of;

(a) a CDRH1 of SEQ ID NOs;

136-147;

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

(c) a CDRH1 amino acid sequence selected from the group consisting of

GYTX₁TSYGIS (SEQ ID NO;

307), wherein

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

(2) CDRH2 selected from the group consisting of;

(a) a CDRH2 of SEQ ID NOs;

148-164;

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

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

WISAYNGNX₁NYAQKX₂QG (SEQ ID NO;

308), wherein

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

X₂ is selected from the group consisting of L and F;

(3) a CDRL1 selected from the group consisting of;

(a) a CDRL1 of SEQ ID NOs;

191-210;

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

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

KSSX₁GVLX₂SSX₃NKNX₄LA (SEQ ID NO;

310), wherein

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

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

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

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

(4) a CDRL2 selected from the group consisting of

(a) a CDRL2 of SEQ ID NOs;

211-224;

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

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

WASX₁RES (SEQ ID NO;

311), wherein

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

or

(B) an isolated antigen binding protein comprising a CDRH3 of claim 24 (A)(3)(b), a CDRL3 of claim 24 (B)(3)(b), and a CDR selected from the group consisting of;

(1) a CDRH1 selected from the group consisting of;

(a) a CDRH1 of SEQ ID NOs;

136-147;

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

(c) a CDRH1 amino acid sequence selected from the group consisting of

GFTX₁X₂X₃AWMS (SEQ ID NO;

313), wherein

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

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

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

(2) a CDRH2 selected from the group consisting of;

(a) a CDRH2 of SEQ ID NOs;

148-164;

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

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

RIKX₁KTDGX₂TX₃DX₄AAPVKG (SEQ ID NO;

314), wherein

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

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

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

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

(3) a CDRL1 selected from the group consisting of;

(a) a CDRL1 of SEQ ID NOs;

191-210;

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

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

QASQDIX₁NYLN (SEQ ID NO;

316), wherein

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

(4) a CDRL2 selected from the group consisting of

(a) a CDRL2 of SEQ ID NOs;

211-224;

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

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

DX₁SNLEX₂ (SEQ ID NO;

317), wherein

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

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

(C) an isolated antigen binding protein comprising a CDRH3 of claim 24 (A)(3)(c), a CDRL3 of claim 24 (B)(3)(c), and a CDR selected from the group consisting of;

(1) a CDRH1 selected from the group consisting of;

(a) a CDRH1 of SEQ ID NOs;

136-147;

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

(c) a CDRH1 amino acid sequence selected from the group consisting of;

GFTFX₁SYGMH (SEQ ID NO;

319), wherein

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

(2) a CDRH2 selected from the group consisting of;

(a) a CDRH2 of SEQ ID NOs;

148-164;

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

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

VIWYDGSNX₁YYADSVKG (SEQ ID NO;

320), wherein X₁ is selected from the group consisting of E and K;

(3) a CDRL1 selected from the group consisting of;

(a) a CDRL1 of SEQ ID NOs;

191-210;

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

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

QASX₁DIX₂NX₃LN (SEQ ID NO;

322), wherein

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

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

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

(4) a CDRL2 selected from the group consisting of;

(a) a CDRL2 of SEQ ID NOs;

211-224;

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

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

DASNLEX₁ (SEQ ID NO;

323), wherein X₁ is selected from the group consisting of T and I.

26. The isolated antigen binding protein of claim 25, wherein said antigen binding protein comprises:

(A) a first amino acid sequence comprising;

(i) a CDRH3 of claim 24 (A)(3)(a) (SEQ ID NO;

309), a CDRH1 of claim 25 (A)(1)(c) (SEQ ID NO;

307), and a CDRH2 of claim 25 (A)(2)(c) (SEQ ID NO;

308);

(ii) a CDRH3 of claim 24 (A)(3)(b) (SEQ ID NO;

315), a CDRH1 of claim 25 (B)(1)(c) (SEQ ID NO;

313), and a CDRH2 of claim 25 (B)(2)(c) (SEQ ID NO;

314), or

(iii) a CDRH3 of claim 24 (A)(3)(c) (SEQ ID NO;

321), a CDRH1 of claim 25 (c)(1)(c) (SEQ ID NO;

319), and a CDRH2 of claim 25 (C)(2)(c) (SEQ ID NO;

320); and

/or

(B) a second amino acid sequence comprising;

(i) a CDRL3 of claim 24 (B)(3)(a) (SEQ ID NO;

312), a CDRL1 of claim 25 (A)(3)(c) (SEQ ID NO;

310), and a CDRL2 of claim 25 (A)(4)(c) (SEQ ID NO;

311);

(ii) a CDRL3 of claim 24 (B)(3)(b) (SEQ ID NO;

318), a CDRH1 of claim 25 (B)(3)(c) (SEQ ID NO;

316), and a CDRH2 of claim 25 (B)(4)(c) (SEQ ID NO;

317), or

(iii) a CDRL3 of claim 24 (B)(3)(c) (SEQ ID NO;

324), a CDRL1 of claim 25 (c)(3)(c) (SEQ ID NO;

322), and a CDRL2 of claim 25 (C)(4)(c) (SEQ ID NO;

323).

27. The isolated antigen binding protein of claim 26, wherein said first amino acid sequence is covalently bonded to said second amino acid sequence.

28. The isolated antigen binding protein of claim 26, wherein said first amino acid sequence comprises said CDRH3 of SEQ ID NOs:

165-190, CDRH2 of SEQ ID NOs;

148-164, and CDRH1 of SEQ ID NOs;

136-147, and said second amino acid sequence comprises said CDRL3 of SEQ ID NOs;

225-246, CDRL2 of SEQ ID NOs;

211-224, and CDRL1 of SEQ ID NOs;

191-210.

29. The isolated antigen binding protein of claim 28, wherein said first amino acid sequence comprises all three heavy chain CDR amino acid sequences (i.e., a CDRH1, a CDHR2, and a CDRH3) included in one of SEQ ID NOs:

4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35; and

/or wherein said second amino acid sequence comprises all three light chain CDR amino acid sequences (i.e., a CDRL1, a CDRL2, and a CDRL3) included in one of SEQ ID NOs;

36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, or 69.

30. The isolated antigen binding protein of claim 29, wherein said first and second amino acid sequence comprise:

(1) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

4 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

36;

(2) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

5 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

66;

(3) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

6 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

38;

(4) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

7 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

39;

(5) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

8 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

40;

(6) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

9 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

41;

(7) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

10 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

42;

(8) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

11 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

43

(9) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

12 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

67;

(10) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

13 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

45;

(11) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

14 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

46;

(12) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

15 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

47

(13) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

17 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

48;

(14) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

18 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

49;

(15) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

19 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

50;

(16) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

20 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

51;

(17) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

21 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

52;

(18) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

22 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

53;

(19) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

23 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

55;

(20) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

24 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

54;

(21) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

25 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

56;

(22) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

27 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

57;

(23) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

28 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

58;

(24) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

29 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

59;

(25) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

30 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

60;

(26) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

31 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

61;

(27) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

32 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

62;

(28) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

33 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

63

(29) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

34 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

64;

or

(30) a CDRH1, CDRH2, and CDRH3 included in SEQ ID NO;

35 and a CDRL1, CDRL2, and CDRL3 included in SEQ ID NO;

65.

63. An antigen binding protein that comprises a CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and a CDRL3 each with a sequence as specified in a line of Table 4C.

64. The antigen binding protein of claim 63 that comprises a VH and a VL, wherein the VH and VL have the amino acid sequence as specified in a line of Table 4C.

65. The antigen binding protein of claim 64 that is an antibody that comprises two identical VH and two identical VL, wherein the VH and VL have the amino acid sequence as specified in a line of Table 4C.

66. An antigen binding protein that competes with an antibody of claim 63.

67. An antigen binding protein that competes with an antibody of claim 65.