IP Library › Granted Patent US 8,679,502

Granted Patent B2

US 8,679,502 · App. 12/681,396 · Granted Mar 25, 2014

Monoclonal antibodies that bind to HGM-CSF and medical compositions comprising same

Inventors: Kenzo Takada (Sapporo, JP); Kantou Nakajima (Sapporo, JP); Barbara Kistler (Ingelheim Am Rhein, DE); John Park (Ingelheim Am Rhein, DE)

Assignees: Evec Inc.; Boehringer Ingelheim International GmbH

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Quick Facts

Patent No.: US 8,679,502
App. No.: 12/681,396
Granted: Mar 25, 2014
Kind: B2

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Abstract

Disclosed herein are anti-hGM-CSF monoclonal antibodies and antigen-binding fragments of such antibodies, with improved neutralizing capacity to hGM-CSF activity. Pharmaceutical compositions comprising such an antibody or antigen-binding fragment are also provided. The present invention is useful for the treatment of various diseases that are associated with aberrant expression of hGM-CSF.

Claims (94)

1. An isolated anti-hGM-CSF monoclonal antibody or antigen-binding fragment thereof, said antibody or antigen-binding fragment thereof comprising:

(a) a heavy chain comprising a V H -CDR1-containing sequence, a V H -CDR2-containing sequence, and a V H -CDR3-containing sequence, wherein:

(i) the V H -CDR1-containing sequence is SYGMH (SEQ ID NO: 4),

(ii) the V H -CDR2-containing sequence is LTYHHGNRKFYADSVRG (SEQ ID NO: 5), and

(iii) the V H -CDR3-containing sequence is ESMGAINDN (SEQ ID NO: 6); and

(b) a light chain comprising a V L -CDR1-containing sequence, a V L -CDR2-containing sequence, and a V L -CDR3-containing sequence, wherein:

(i) the V L -CDR1-containing sequence is IGNNNNIGSHAVG (SEQ ID NO: 7),

(ii) the V L -CDR2-containing sequence is GRSPPS (SEQ ID NO: 8), and

(iii) the V L -CDR3-containing sequence is STWDSSLSAVV (SEQ ID NO: 9).

2. The antibody or antigen-binding fragment thereof as claimed in claim 1 , wherein the antibody or antigen-binding fragment thereof binds to human GM-CSF with a K D of less than 400 pM.

3. The antibody or antigen-binding fragment thereof as claimed in claim 2 , wherein the K D is less than 160 pM.

4. The antibody or antigen-binding fragment thereof as claimed in claim 1 , wherein the antibody or antigen-binding fragment thereof neutralizes hGM-CSF activity, such that the antibody or antigen-binding fragment thereof has an IC50 value of less than 100 pM as determined in a TF-1 proliferation assay at ED80.

5. The antibody or antigen-binding fragment thereof as claimed in claim 4 , wherein the IC50 value is less than 30 pM.

6. The antibody or antigen-binding fragment thereof as claimed in claim 5 , wherein the IC50 value is less than 20 pM.

7. The antibody or antigen-binding fragment thereof as claimed in claim 1 , further comprising a signal sequence.

8. The antibody or antigen-binding fragment thereof as claimed in claim 7 , wherein the signal sequence is selected from the group consisting of SEQ ID NOs: 324, 325, and 326.

9. The antibody or antigen-binding fragment thereof as claimed in claim 1 , wherein the heavy chain is selected from the group consisting of gamma 1 (γ 1 ), gamma 2 (γ 2 ), gamma 3 (γ 3 ), and gamma 4 (γ 4 ).

10. The antibody or antigen-binding fragment thereof as claimed in claim 9 , wherein the heavy chain is gamma 1 (γ 1 ).

11. The antibody or antigen-binding fragment thereof as claimed in claim 9 , wherein the light chain is a lambda light chain.

12. The antibody or antigen-binding fragment thereof as claimed in claim 1 , wherein the heavy chain has the amino acid sequence SEQ ID NO: 46.

13. The antibody or antigen-binding fragment thereof as claimed in claim 12 , wherein the light chain is a lambda light chain.

14. The antibody or antigen-binding fragment thereof as claimed in claim 13 , wherein the light chain has the amino acid sequence SEQ ID NO:36.

15. The antibody or antigen-binding fragment thereof as claimed in claim 12 , wherein the light chain is a kappa light chain.

16. The antibody or antigen-binding fragment thereof as claimed in claim 12 , further comprising a signal sequence.

17. The antibody or antigen-binding fragment thereof as claimed in claim 16 , wherein the signal sequence is selected from the group consisting of SEQ ID NOs: 324, 325, and 326.

18. The antibody or antigen-binding fragment thereof as claimed in claim 1 , wherein the heavy chain has the amino acid sequence SEQ ID NO: 51.

19. The antibody or antigen-binding fragment thereof as claimed in claim 18 , wherein the light chain is a lambda light chain.

20. The antibody or antigen-binding fragment thereof as claimed in claim 19 , wherein the light chain has the amino acid sequence SEQ ID NO:36.

21. The antibody or antigen-binding fragment thereof as claimed in claim 18 , wherein the light chain is a kappa light chain.

22. The antibody or antigen-binding fragment thereof as claimed in claim 18 , further comprising a signal sequence.

23. The antibody or antigen-binding fragment thereof as claimed in claim 22 , wherein the signal sequence is selected from the group consisting of SEQ ID NOs: 324, 325, and 326.

24. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof as claimed in claim 1 , and a pharmaceutically acceptable carrier.

25. A kit comprising the composition as claimed in claim 24 , and one or more containers containing the composition.

26. A kit comprising: (a) the antibody or antigen-binding fragment thereof as claimed in claim 1 ; and (b) one or more containers containing the antibody or antigen-binding fragment thereof.

27. An isolated nucleic acid encoding the anti-hGM-CSF monoclonal antibody or antigen-binding fragment thereof as claimed in claim 1 .

28. The isolated nucleic acid of claim 27 , wherein the nucleic acid is a DNA.

29. A vector comprising the DNA of claim 28 .

30. An isolated host cell comprising the vector of claim 29 , wherein the vector is an expression vector.

31. An isolated anti-hGM-CSF monoclonal antibody or antigen-binding fragment thereof, said antibody or antigen-binding fragment thereof comprising a heavy chain variable region having a heavy chain variable region sequence and a light chain variable region having a light chain variable region sequence, wherein the heavy chain variable region sequence is SEQ ID NO: 348, and wherein the light chain variable region sequence is SEQ ID NO: 365.

32. The antibody or antigen-binding fragment thereof as claimed in claim 31 , wherein said antibody belongs to IgG 1 (λ) class (subclass).

33. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof as claimed in claim 31 , and a pharmaceutically acceptable carrier.

34. A kit comprising the composition as claimed in claim 33 , and one or more containers containing the composition.

35. An isolated anti-hGM-CSF monoclonal antibody or antigen-binding fragment thereof, said antibody or antigen-binding fragment thereof comprising a heavy chain variable region having a heavy chain variable region sequence and a light chain variable region having a light chain variable region sequence, wherein the heavy chain variable region sequence is SEQ ID NO: 361, and wherein the light chain variable region sequence is SEQ ID NO: 365.

36. The antibody or antigen-binding fragment thereof as claimed in claim 35 , wherein said antibody belongs to IgG 1 (λ) class (subclass).

37. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof as claimed in claim 35 , and a pharmaceutically acceptable carrier.

38. A kit comprising the composition as claimed in claim 37 , and one or more containers containing the composition.

39. An isolated anti-hGM-CSF monoclonal antibody comprising a heavy chain having a heavy chain sequence and a light chain having a light chain sequence, wherein the heavy chain sequence is SEQ ID NO: 46, and wherein the light chain sequence is SEQ ID NO: 36.

40. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof as claimed in claim 39 , and a pharmaceutically acceptable carrier.

41. A kit comprising the composition as claimed in claim 40 , and one or more containers containing the composition.

42. An isolated anti-hGM-CSF monoclonal antibody comprising a heavy chain having a heavy chain sequence and a light chain having a light chain sequence, wherein the heavy chain sequence is SEQ ID NO: 51, and wherein the light chain sequence is SEQ ID NO: 36.

43. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof as claimed in claim 42 , and a pharmaceutically acceptable carrier.

44. A kit comprising the composition as claimed in claim 43 , and one or more containers containing the composition.

45. A vector comprising a DNA sequence encoding a heavy chain of an anti-hGM-CSF antibody comprising a V H -CDR1-containing sequence, a V H -CDR2-containing sequence, and a V H -CDR3-containing sequence, wherein:

(i) the V H -CDR1-containing sequence is SYGMH (SEQ ID NO: 4),

(ii) the V H -CDR2-containing sequence is LTYHHGNRKFYADSVRG (SEQ ID NO: 5), and

(iii) the V H -CDR3-containing sequence is ESMGAINDN (SEQ ID NO: 6).

46. A vector comprising a DNA sequence encoding a light chain of an anti-hGM-CSF antibody comprising a V L -CDR1-containing sequence, a V L -CDR2-containing sequence, and a V L -CDR3-containing sequence, wherein:

(i) the V L -CDR1-containing sequence is IGNNNNIGSHAVG (SEQ ID NO: 7),

(ii) the V L -CDR2-containing sequence is GRSPPS (SEQ ID NO: 8), and

(iii) the V L -CDR3-containing sequence is STWDSSLSAVV (SEQ ID NO: 9).

47. A method for producing an anti-hGM-CSF monoclonal antibody or antigen-binding fragment thereof that binds hGM-CSF, wherein the antibody or antigen-binding fragment thereof comprises at least a V H -CDR1-containing sequence, a V H -CDR2-containing sequence, a V H -CDR3-containing sequence, a V L -CDR1-containing sequence, a V L -CDR2-containing sequence, and a V L -CDR3-containing sequence, in an isolated host cell, the method comprising:

(i) obtaining the isolated host cell comprising at least one DNA sequence encoding at least the V H -CDR1-containing sequence, the V H -CDR2-containing sequence, the V H -CDR3-containing sequence, the V L -CDR1-containing sequence, the V L -CDR2-containing sequence, and the V L -CDR3-containing sequence, wherein:

(a) the V H -CDR1-containing sequence is SYGMH (SEQ ID NO: 4),

(b) the V H -CDR2-containing sequence is LTYHHGNRKFYADSVRG (SEQ ID NO: 5),

(d) the V L -CDR1-containing sequence is IGNNNNIGSHAVG (SEQ ID NO: 7),

(e) the V L -CDR2-containing sequence is GRSPPS (SEQ ID NO: 8), and

(f) the V L -CDR3-containing sequence is STWDSSLSAVV (SEQ ID NO: 9); and

(ii) culturing the isolated host cell under conditions suitable for expression of DNA and production of the antibody or antigen binding fragment thereof.

48. The method of claim 47 , further comprising isolating the antibody or antigen-binding fragment thereof.

49. The method of claim 48 , further comprising preparing a composition comprising said antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier.

50. The method of claim 47 , wherein the at least one DNA encodes a heavy chain or portion thereof and a light chain or portion thereof, wherein the heavy chain or portion thereof has a sequence selected from the group consisting of SEQ ID NOs: 46 and 348, and wherein the light chain or portion thereof has a sequence selected from the group consisting of SEQ ID NOs: 36 and 365.

51. The method of claim 50 , further comprising isolating the antibody or antigen-binding fragment thereof.

52. The method of claim 51 , further comprising preparing a composition comprising said antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier.

53. The method of claim 47 , wherein the at least one DNA encodes a heavy chain or portion thereof and a light chain or portion thereof, wherein the heavy chain or portion thereof has a sequence selected from the group consisting of SEQ ID NOs: 51 and 361, and wherein the light chain or portion thereof has a sequence selected from the group consisting of SEQ ID NOs: 36 and 365.

54. The method of claim 53 , further comprising isolating the antibody or antigen-binding fragment thereof.

55. The method of claim 54 , further comprising preparing a composition comprising said antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier.

56. A composition comprising an isolated anti-hGM-CSF monoclonal antibody or antigen-binding fragment thereof, said antibody or antigen-binding fragment thereof comprising: