Anti-CD26 antibodies and methods of use thereof

• US 20070105771A1
• Filed: 07/24/2006
• Published: 05/10/2007
• Est. Priority Date: 07/22/2005
• Status: Active Grant

• Current Assignee: Y's AC Co., Ltd.
• Original Assignee: Y's Therapeutics Co., Ltd.
• Inventors: Li, Yan, Zhong, Pingyu, Hsieh, Mark, Aoyagi, Teikichi, Morimoto, Chikao, Luo, Peter, Wang, Kevin
• Granted Patent: US 7,462,698 B2
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• 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 2317/55 Fab or Fab'
• 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 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 2333/70596 Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 33/574 : for cancer
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides novel anti-CD26 antibodies and other, related polypeptides, as well as novel polynucleotides encoding the antibodies and polypeptides. The invention also provides methods of making the antibodies and polypeptides. Compositions and cells comprising the antibodies or polypeptides are further provided. Methods of using the antibodies and/or polypeptides, such as to inhibit cell proliferation and in the treatment of conditions associated with CD26, are also provided.

Claims

1. A polypeptide, comprising:

(a) one or more heavy chain CDRs selected from the group consisting of (i) a heavy chain CDR1 comprising the sequence GX₁X₂LX₃TYGVH (SEQ ID NO;

31), wherein X₁ is F or Y, X₂ is S or T, and X₃ is T, N, or S, (ii) a heavy chain CDR2 comprising the sequence VIWGX₁GRTDYDX₂X₃FMS (SEQ ID NO;

32), wherein X₁ is G or D, X₂ is A or S, and X₃ is A or S, and (iii) a heavy chain CDR3 comprising the sequence X₁RHDWFDY (SEQ ID NO;

33), wherein X₁ is N or S;

(b) one or more light chain CDRs selected from the group consisting of (i) a light chain CDR1 comprising the sequence X₁ASQX₂IRNX₃LN (SEQ ID NO;

34), wherein X₁ is S or R, X₂ is G or D, and X₃ is S or N, (ii) a light chain CDR2 comprising the sequence YSSNLX₁X₂ (SEQ ID NO;

35), wherein X₁ is H or Q and X₂ is S or T, and (iii) a light chain CDR3 comprising the sequence QQSX₁KLPX₂T (SEQ ID NO;

36), wherein X₁ is I or N and X₂ is F or L;

or

one or more heavy chain CDRs as indicated in (a) and one or more light chain CDRs as indicated in (b);

wherein the polypeptide does not comprise both a heavy chain variable region of the sequence QVKLQESGPGLVQPSQTLSITCTVSGFSLTTYGVHWVRQSPGKGLEWLGVIWGGGRTD YDAAFISRLSISKDNSKSQVFFKMNSLQANDTAIYYCVRNRHDWFDYWGQGTTVTVSS (SEQ ID NO;

90) and a light chain variable region of the sequence DIQMTQSPSSLSASLGDRVTITCSASQGIRNSLNWYQQKPDGAVKLLIYYSSNLHSGVPS RFSGSGSGTDFSLTISNLEPEDIATYYCQQSIKLPFTFGSGTKLEIK (SEQ ID NO;

91).

2. The polypeptide of claim 1, which comprises one or more heavy chain CDRs as indicated in (a).

3. The polypeptide of claim 2, which comprises

(i) a heavy chain CDR1 comprising the sequence GX₁X₂LX₃TYGVH (SEQ ID NO:

31), wherein X₁ is F or Y, X₂ is S or T, and X₃ is T, N, or S, (ii) a heavy chain CDR2 comprising the sequence VIWGX₁GRTDYDX₂X₃FMS (SEQ ID NO;

32), wherein X₁ is G or D, X₂ is A or S, and X₃ is A or S, and (iii) a heavy chain CDR3 comprising the sequence X₁RHDWFDY (SEQ ID NO;

33), wherein X₁ is N or S.

4. The polypeptide of claim 3, which further comprises

(i) a light chain CDR1 comprising the sequence X₁ASQX₂IRNX₃LN (SEQ ID NO:

34), wherein X₁ is S or R, X₂ is G or D, and X₃ is S or N, (ii) a light chain CDR2 comprising the sequence YSSNLX₁X₂ (SEQ ID NO;

35), wherein X₁ is H or Q and X₂ is S or T, and (iii) a light chain CDR3 comprising the sequence QQSX₁KLPX₂T (SEQ ID NO;

36), wherein X₁ is I or N and X₂ is F or L.

5. The polypeptide of claim 1, wherein the heavy chain CDR1 comprises a sequence selected from the group consisting of GFSLTTYGVH (SEQ ID NO:

55), GFSLSTYGVH (SEQ ID NO;

56), and GYSLTTYGVH (SEQ ID NO;

57).

6. The polypeptide of claim 1, wherein the heavy chain CDR2 comprises a sequence selected from the group consisting of VIWGDGRTDYDAAFMS (SEQ ID NO:

58) and VIWGDGRTDYDSSFMS (SEQ ID NO;

59).

7. The polypeptide of claim 1, wherein the heavy chain CDR3 comprises the sequence NRHDWFDY (SEQ ID NO:

60).

8. The polypeptide of claim 1, which comprises

(a) heavy chain CDRs comprising

(i) a CDR1 comprising the sequence GFSLTTYGVH (SEQ ID NO:

55),

(ii) a CDR2 comprising the sequence VIWGDGRTDYDAAFMS (SEQ ID NO;

58), and

(iii) a CDR3 comprising the sequence NRHDWFDY (SEQ ID NO;

60);

(b) heavy chain CDRs comprising

(i) a CDR1 comprising the sequence GFSLSTYGVH (SEQ ID NO;

56),

(ii) a CDR2 comprising the sequence VIWGDGRTDYDAAFMS (SEQ ID NO;

58), and

(iii) a CDR3 comprising the sequence NRHDWFDY (SEQ ID NO;

60);

or

(c) heavy chain CDRs comprising

(i) a CDR1 comprising the sequence GYSLTTYGVH (SEQ ID NO;

57),

(ii) a CDR2 comprising the sequence VIWGDGRTDYDSSFMS (SEQ ID NO;

59), and

(iii) a CDR3 comprising the sequence NRHDWFDY (SEQ ID NO;

60).

9. The polypeptide of claim 8, which further comprises

(a) light chain CDRs comprising

(i) a CDR1 comprising the sequence RASQDIRNNLN (SEQ ID NO:

61),

(ii) a CDR2 comprising the sequence YSSNLHS (SEQ ID NO;

64), and

(iii) a CDR3 comprising the sequence QQSIKLPLT (SEQ ID NO;

67);

(b) light chain CDRs comprising

(i) a CDR1 comprising the sequence RASQGIRNNLN (SEQ ID NO;

62),

(ii) a CDR2 comprising the sequence YSSNLQS (SEQ ID NO;

65), and

(iii) a CDR3 comprising the sequence QQSIKLPFT (SEQ ID NO;

68);

or

(c) light chain CDRs comprising

(i) a CDR1 comprising the sequence SASQDIRNSLN (SEQ ID NO;

63),

(ii) a CDR2 comprising the sequence YSSNLHT (SEQ ID NO;

66), and

(iii) a CDR3 comprising the sequence QQSNKLPLT (SEQ ID NO;

69).

10. The polypeptide of claim 1, which comprises one or more light chain CDRs as indicated in (b).

11. The polypeptide of claim 10, which comprises

(i) a light chain CDR1 comprising the sequence X₁ASQX₂IRNX₃LN (SEQ ID NO:

34), wherein X₁ is S or R, X₂ is G or D, and X₃ is S or N, (ii) a light chain CDR2 comprising the sequence YSSNLX₁X₂ (SEQ ID NO;

35), wherein X₁ is H or Q and X₂ is S or T, and (iii) a light chain CDR3 comprising the sequence QQSX₁KLPX₂T (SEQ ID NO;

36), wherein X₁ is I or N and X₂ is F or L.

12. The polypeptide of claim 10, wherein the light chain CDR1 comprises a sequence selected from the group consisting of RASQDIRNNLN (SEQ ID NO:

61), RASQGIRNNLN (SEQ ID NO;

62), and SASQDIRNSLN (SEQ ID NO;

63).

13. The polypeptide of claim 10, wherein the light chain CDR2 comprises a sequence selected from the group consisting of YSSNLHS (SEQ ID NO:

64), YSSNLQS (SEQ ID NO;

65) and YSSNLHT (SEQ ID NO;

66).

14. The polypeptide of claim 10, wherein the light chain CDR3 comprises a sequence selected from the group consisting of QQSIKLPLT (SEQ ID NO:

67), QQSIKLPFT (SEQ ID NO;

68), and QQSNKLPLT (SEQ ID NO;

69).

15. The polypeptide of claim 10, which comprises

(a) light chain CDRs comprising

(i) a CDR1 comprising the sequence RASQDIRNNLN (SEQ ID NO:

61),

(ii) a CDR2 comprising the sequence YSSNLHS (SEQ ID NO;

64), and

(iii) a CDR3 comprising the sequence QQSIKLPLT (SEQ ID NO;

67);

(b) light chain CDRs comprising

(i) a CDR1 comprising the sequence RASQGIRNNLN (SEQ ID NO;

62),

(ii) a CDR2 comprising the sequence YSSNLQS (SEQ ID NO;

65), and

(iii) a CDR3 comprising the sequence QQSIKLPFT (SEQ ID NO;

68);

or

(c) light chain CDRs comprising

(i) a CDR1 comprising the sequence SASQDIRNSLN (SEQ ID NO;

63),

(ii) a CDR2 comprising the sequence YSSNLHT (SEQ ID NO;

66), and

(iii) a CDR3 comprising the sequence QQSNKLPLT (SEQ ID NO;

69).

16. The polypeptide of claim 1, which comprises one or more heavy chain CDRs as indicated in (a) and one or more light chain CDRs as indicated in (b).

17. The polypeptide of claim 1, wherein the polypeptide further comprises

(a) one or more heavy chain framework regions selected from the group consisting of (i) a heavy chain FR1 comprising the sequence EVQLVX₁SGX₂X₃X₄X₅QPGX₆X₇LRLX₈CX₉AS (SEQ ID NO:

37), wherein X₁ is E or Q, X₂ is A or G, X₃ is G or E, X₄ is L or V, X₅ is V, K, or E, X₆ is G or E, X₇ is T or S, X₈ is T or S, and X₉ is T or K;

(ii) a heavy chain FR2 comprising the sequence WVRQAPGKGLEWX₁G (SEQ ID NO;

38), wherein X₁ is V or M, (iii) a heavy chain FR3 comprising the sequence RVTISX₁DX₂SKX₃TX₄YLQX₅NSLRAEDTAVYYCX₆R (SEQ ID NO;

39), wherein X₁ is K or R, X₂ is N or T, X₃ is S or N, X₄ is V or A, X₅ is M or L, and X₆ is V, M, or T, and (iv) a heavy chain FR4 comprising the sequence WGQGTTVTVSS (SEQ ID NO;

40);

(b) one or more light chain framework regions selected from the group consisting of (i) a light chain FR1 comprising the sequence X₁IX₂X₃TQSPSSLSX₄X₅X₆GX₇RX₈TIX₉C (SEQ ID NO;

41), wherein X₁ is D or E, X₂ is L or E, X₃ is M or L, X₄ is A or V, X₅ is S or T, X₆ is L, P, or A, X₇ is D or E, X₈ is V or A, and X₉ is T or S, (ii) a light chain FR2 comprising the sequence WYQQKPGQAPRLLIY (SEQ ID NO;

     42), (iii) a light chain FR3 comprising the sequence GVPX₁RFSGSGSGTDFTLTISRLX₂X₃EDX₄AX₅YYC (SEQ ID NO;

     43), wherein X₁ is S, D, or A, X₂ is E or Q, X₃ is P or A, X₄ is F or V, and X₅ is T, A, or I, and (iv) a light chain FR4 comprising the sequence FGSGTKVEIK (SEQ ID NO;

44);

or

(c) one or more heavy chain framework regions as indicated in (a) and one or more light chain framework regions as indicated in (b).

25. The polypeptide of claim 1, which is an antibody.

26. The antibody of claim 25, which is a monoclonal antibody.

27. The antibody of claim 25, which is a humanized antibody.

28. The antibody of claim 25, which is an antibody fragment.

29. The antibody of claim 28, wherein the antibody fragment is selected from the group consisting of Fab, Fab′

, Fab′

-SH, Fv, scFv and F(ab′

)₂.

30. The polypeptide of claim 1, which is an antibody chain.

31. The polypeptide of claim 1 which is not a murine monoclonal antibody.

32. The polypeptide of claim 1, which is isolated.

33. The polypeptide of claim 1, which binds CD26.

34. The polypeptide of claim 33, wherein the CD26 is human CD26.

35. The polypeptide of claim 34, which binds to human CD26 with a K_D of about 6 nM or less.

36. A polynucleotide encoding the polypeptide of claim 1.

37. A vector comprising the polynucleotide of claim 36.

38. A host cell comprising the polynucleotide of claim 36.

41. A pharmaceutical composition comprising the polypeptide of claim 1 and a pharmaceutically acceptable excipient.

42. A method of inhibiting proliferation of a cell expressing CD26 comprising contacting the cell with the polypeptide of claim 1.

43. A method of treating a condition associated with CD26 expression in a subject, comprising administering an effective amount of a composition comprising the polypeptide of claim 1 to the subject.

44. The method of claim 43, wherein the condition is an autoimmune disease.

45. The method of claim 43, wherein the condition is graft versus host disease.

46. The method of claim 43, wherein the condition is a cancer.

47. The method of claim 46, wherein the cancer is a hematological malignancy.

48. The method of claim 46, wherein the subject has a CD26-expressing tumor or has had a CD26-expressing tumor removed.

49. The method of claim 46, wherein the cancer is lymphoma, kidney cancer, prostate cancer, or lung cancer.

50. A method of inhibiting tumor growth in a subject who has a CD26-expressing tumor or who has had a CD26-expressing tumor removed, comprising administering an effective amount of a composition comprising the polypeptide of claim 1 to the subject.

51. A method of inhibiting metastasis of CD26-expressing cancer cells in a subject, comprising administering an effective amount of a composition comprising the polypeptide of claim 1 to the subject.

52. The method of claim 43, wherein the subject is human.

62. The method of claim 46, further comprising the step of treating the subject with chemotherapy, radiation, surgery, hormone therapy, or additional immunotherapy.

64. The polypeptide of claim 9, which comprises (a) heavy chain CDRs comprising:

(i) a CDR1 comprising the sequence GFSLTTYGVH (SEQ ID NO;

55);

(ii) a CDR2 comprising the sequence VIWGDGRTDYDAAFMS (SEQ ID NO;

58); and

(iii) a CDR3 comprising the sequence NRHDWFDY (SEQ ID NO;

60); and

(b) light chain CDRs comprising;

(i) a CDR1 comprising the sequence RASQGIRNNLN (SEQ ID NO;

62);

(ii) a CDR2 comprising the sequence YSSNLQS (SEQ ID NO;

65); and

(iii) a CDR3 comprising the sequence QQSIKLPFT (SEQ ID NO;

68).

18. A polypeptide comprising:

(a) an amino acid sequence consisting of

EVQLVX₁SGX₂X₃X₄X₅QPGX₆X₇LRLX₈CX₉ASGX₁₀X₁₁ILX₁₂TYGVHWVRQAPGKG LEWX₁₃GVIWGX₁₄GRTDYDX₁₅X₁₆FMSRVTISX₁₇DX₁₈SKX₁₉TX₂₀YLQX₂₀NSLRAEDTAV YYCX₂₂RX₂₃RHDWFDYWGQGTTVTVSS (SEQ ID NO;

29), wherein X₁ is E or Q, X₂ is A or G, X₃ is G or E, X₄ is L or V, X₅ is V, K, or E, X₆ is G or E, X₇ is T or S, X₈ is T or S, X₉ is T or K, X₁₀ is F or Y, X₁₁ is S or T, X₁₂ is T, N, or S, X₁₃ is V or M, X₁₄ is G or D, X₁₅ is A or S, X₁₆ is A or S, X₁₇ is K or R, X₁₈ is N or T, X₁₉ is S or N, X₂₀ is V or A, X₂₁ is M or L, X₂₂ is V, M, or T, and X₂₃ is N or S;

(b) an amino acid sequence consisting of X₁₁X₂X₃TQSPSSLSX₄X₅X₆GX₇RX₈TIX₉CX₁₀ASQX₁₁IRNX₁₂LNWYQQKPGQAPRLL IYYSSNLX₁₃X₁₄GVPX₁₅RFSGSGSGTDFTLTISRLX₁₆X₁₇EDX₁₈AX₁₉YYCQQSX₂₀KLPX₂₁TF GSGTKVEIK (SEQ ID NO;

30), wherein X₁ is D or E, X₂ is L or E, X₃ is M or L, X₄ is A or V, X₅ is S or T, X₆ is L, P, or A, X₇ is D or E, X₈ is V or A, X₉ is T or S, X₁₀ is S or R, X₁₁ is G or D, X₁₂ is S or N, X₁₃ is H or Q, X₁₄ is S or T, X₁₅ is S, D, or A, X₁₆ is E or Q, X₁₇ is P or A, X₁₈ is F or V, X₁₉ is T, A, or I, X₂₀ is I or N and X₂₁ is F or L;

or

(c) both the amino acid sequence indicated in (a) and the amino acid sequence indicated in (b).

53. The polypeptide of claim 18, 19, or 23, which is an antibody.

54. The polypeptide of claim 18, 19, or 23, which binds CD26.

55. A polynucleotide encoding the polypeptide of claim 18, 19, or 23.

56. A pharmaceutical composition comprising the polypeptide of claim 18, 19, or 23 and a pharmaceutically acceptable excipient.

57. A method of inhibiting proliferation of a cell expressing CD26 comprising contacting the cell with the polypeptide of claim 18, 19, or 23.

58. A method of treating a condition associated with CD26 expression in a subject, comprising administering an effective amount of a composition comprising the polypeptide of claim 18, 19, or 23 to the subject.

59. The method of claim 58, wherein the condition is cancer.

60. A method of inhibiting tumor growth in a subject who has a CD26-expressing tumor or who has had a CD26-expressing tumor removed, comprising administering an effective amount of a composition comprising the polypeptide of claim 18, 19, or 23 to the subject.

61. A method of inhibiting metastasis of CD26-expressing cancer cells in a subject, comprising administering an effective amount of a composition comprising the polypeptide of claim 18, 19, or 23 to the subject.

63. The method of claim 59, further comprising the step of treating the subject with chemotherapy, radiation, surgery, hormone therapy, or additional immunotherapy.

19. A polypeptide, comprising:

(a) an amino acid sequence having at least about 80% identity to an amino acid sequence selected from the group consisting of SEQ ID NOS;

15-21;

(b) an amino acid sequence having at least about 80% identity to an amino acid sequence selected from the group consisting of SEQ ID NOS;

22-28;

or

(c) an amino acid sequence as indicated in (a) and an amino acid sequence as indicated in (b);

wherein the polypeptide does not comprise both a heavy chain variable region of the sequence QVKLQESGPGLVQPSQTLSITCTVSGFSLTTYGVHWVRQSPGKGLEWLGVIWGGGRTD YDAAFISRLSISKDNSKSQVFFKMNSLQANDTAIYYCVRNRHDWFDYWGQGTTVTVSS (SEQ ID NO;

90) and a light chain variable region of the sequence DIQMTQSPSSLSASLGDRVTITCSASQGIRNSLNWYQQKPDGAVKLLIYYSSNLHSGVPS RFSGSGSGTDFSLTISNLEPEDIATYYCQQSIKLPFTFGSGTKLEIK (SEQ ID NO;

91).

20. The polypeptide of claim 19, which comprises

(a) an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOS:

15-21;

(b) an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOS;

22-28;

or

(c) an amino acid sequence as indicated in (a) and an amino acid sequence as indicated in (b).

21. The polypeptide of claim 20, which comprises

(a) an amino acid sequence selected from the group consisting of SEQ ID NOS:

15-21;

(b) an amino acid sequence selected from the group consisting of SEQ ID NOS;

22-28;

or

(c) an amino acid sequence as indicated in (a) and an amino acid sequence as indicated in (b).

22. The polypeptide of claim 21, which comprises

(a) a heavy chain variable region comprising amino acid sequence SEQ ID NO:

26 and a light chain variable region comprising amino acid sequence SEQ ID NO;

15;

(b) a heavy chain variable region comprising amino acid sequence SEQ ID NO;

22 and a light chain variable region comprising amino acid sequence SEQ ID NO;

18;

(c) a heavy chain variable region comprising amino acid sequence SEQ ID NO;

28 and a light chain variable region comprising amino acid sequence SEQ ID NO;

19;

or

(d) a heavy chain variable region comprising amino acid sequence SEQ ID NO;

23 and a light chain variable region comprising amino acid sequence SEQ ID NO;

19.

23. A polypeptide comprising:

(a) one or more heavy chain framework regions selected from the group consisting of (i) a heavy chain FR1 comprising the sequence EVQLVX₁SGX₂X₃X₄X₅QPGX₆X₇LRLX₈CX₉AS (SEQ ID NO;

37), wherein X₁ is E or Q, X₂ is A or G, X₃ is G or E, X₄ is L or V, X₅ is V, K, or E, X₆ is G or E, X₇ is T or S, X₈ is T or S, and X₉ is T or K;

(ii) a heavy chain FR2 comprising the sequence WVRQAPGKGLEWX₁G (SEQ ID NO;

38), wherein X₁ is V or M, (iii) a heavy chain FR3 comprising the sequence RVTISX₁DX₂SKX₃TX₄YLQX₅NSLRAEDTAVYYCX₆R (SEQ ID NO;

39), wherein X₁ is K or R, X₂ is N or T, X₃ is S or N, X₄ is V or A, X₅ is M or L, and X₆ is V, M, or T, and (iv) a heavy chain FR4 comprising the sequence WGQGTTVTVSS (SEQ ID NO;

40);

(b) one or more light chain framework regions selected from the group consisting of (i) a light chain FR1 comprising the sequence X₁IX₂X₃TQSPSSLSX₄X₅X₆GX₇RX₈TIX₉C (SEQ ID NO;

41), wherein X₁ is D or E, X₂ is L or E, X₃ is M or L, X₄ is A or V, X₅ is S or T, X₆ is L, P, or A, X₇ is D or E, X₈ is V or A, and X₉ is T or S, (ii) a light chain FR2 comprising the sequence WYQQKPGQAPRLLIY (SEQ ID NO;

     42), (iii) a light chain FR3 comprising the sequence GVPX₁RFSGSGSGTDFTLTISRLX₂X₃EDX₄AX₅YYC (SEQ ID NO;

     43), wherein X₁ is S, D, or A, X₂ is E or Q, X₃ is P or A, X₄ is F or V, and X₅ is T, A, or I, and (iv) a light chain FR4 comprising the sequence FGSGTKVEIK (SEQ ID NO;

44);

or

(c) one or more heavy chain framework regions as indicated in (a) and one or more light chain framework regions as indicated in (b);

wherein the polypeptide does not comprise both a heavy chain variable region of the sequence QVKLQESGPGLVQPSQTLSITCTVSGFSLTTYGVHWVRQSPGKGLEWLGVIWGGGRTD YDAAFISRLSISKDNSKSQVFFKMNSLQANDTAIYYCVRNRHDWFDYWGQGTTVTVSS (SEQ ID NO;

90) and a light chain variable region of the sequence DIQMTQSPSSLSASLGDRVTITCSASQGIRNSLNWYQQKPDGAVKLLIYYSSNLHSGVPS RFSGSGSGTDFSLTISNLEPEDIATYYCQQSIKLPFTFGSGTKLEIK (SEQ ID NO;

91).

24. An antibody that binds to one or more peptides selected from the group consisting of YSLRWISDHEYLY (SEQ ID NO:

45;

peptide

     6), LEYNYVKQWRHSY (SEQ ID NO;

46;

peptide

     35), TWSPVGHKLAYVW (SEQ ID NO;

47;

peptide

     55), LWWSPNGTFLAYA (SEQ ID NO;

48;

peptide

     84), RISLQWLRRIQNY (SEQ ID NO;

49;

peptide

     132), YVKQWRHSYTASY (SEQ ID NO;

50;

peptide

     37), EEEVFSAYSALWW (SEQ ID NO;

51;

peptide

     79), DYSISPDGQFILL (SEQ ID NO;

52;

peptide

     29), SISPDGQFILLEY (SEQ ID NO;

53;

peptide

     30), and IYVKIEPNLPSYR (SEQ ID NO;

54;

peptide

     63), wherein the antibody does not comprise both a heavy chain variable region of the sequence QVKLQESGPGLVQPSQTLSITCTVSGFSLTTYGVHWVRQSPGKGLEWLGVIWGGGRTD YDAAFISRLSISKDNSKSQVFFKMNSLQANDTAIYYCVRNRHDWFDYWGQGTTVTVSS (SEQ ID NO;

90) and a light chain variable region of the sequence DIQMTQSPSSLSASLGDRVTITCSASQGIRNSLNWYQQKPDGAVKLLIYYSSNLHSGVPS RFSGSGSGTDFSLTISNLEPEDIATYYCQQSIKLPFTFGSGTKLEIK (SEQ ID NO;

91).

39. A polynucleotide comprising a nucleic acid sequence selected from the group consisting of SEQ ID NOS:

1-14.

40. A host cell comprising the polynucleotide of claim 39.

65. An antibody encoded by the plasmid deposited with the ATCC in E. coli as accession number ______.