IP Library › Granted Patent US 9,073,998

Granted Patent B2

US 9,073,998 · App. 12/396,286 · Granted Jul 7, 2015

Antibodies directed to the deletion mutants of epidermal growth factor receptor and uses thereof

Inventors: Richard Weber (San Francisco, CA); Xiao Feng (Union City, CA); Orit Foord (Foster City, CA); Larry Green (San Francisco, CA); Jean M. Gudas (Santa Monica, CA); Bruce Keyt (Hillsborough, CA); Ying Liu (Palo Alto, CA); Palaniswami Rathanaswami (Vancouver, CA); Robert Raya (Fremont, CA); Xiao Dong Yang (Palo Alto, CA); Jose Corvalan (Foster City, CA); Ian Foltz (Burnaby, CA); Xiao-Chi Jia (Los Angeles, CA); Jaspal S. Kang (Surrey, CA); Chadwick T. King (Vancouver, CA); Scott L. Klakamp (Fremont, CA); Qiaojuan Jane Su (San Jose, CA)

Assignee: Amgen Fremont Inc.

C07K16/2863 A61K47/48384 A61K47/48561 A61K47/48746 A61K2039/505 B82Y5/00 C07K2317/92 Y10S435/81 C07K2317/34

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Quick Facts

Patent No.: US 9,073,998
App. No.: 12/396,286
Granted: Jul 7, 2015
Kind: B2

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Abstract

The present invention relates to novel antibodies, particularly antibodies directed against deletion mutants of epidermal growth factor receptor and particularly to the type III deletion mutant, EGFRvIII. The invention also relates to human monoclonal antibodies directed against deletion mutants of epidermal growth factor receptor and particularly to EGFRvIII. Diagnostic and therapeutic formulations of such antibodies, and immunoconjugates thereof, are also provided.

Claims (140)

1. A method of inhibiting cell proliferation associated with the expression of EGFRvIII, wherein the EGFRvIII comprises the amino acid sequence of SEQ ID NO: 56, said method comprising contacting the cell expressing the EGFRvIII with an effective amount of an antibody that binds to LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII, wherein said antibody is conjugated to a toxin selected from a Maytansinoid and saporin, and wherein the antibody is

a) an antibody comprising a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 142; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 142; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 142; and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 144; a light chain CDR2 that a CDR2 in SEQ ID NO: 144; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 144,

b) an antibody comprising a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 2; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 2; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 2; and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 19; a light chain CDR2 that is a CDR2 in SEQ ID NO: 19; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 19,

c) an antibody comprising a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 4; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 4; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 4; and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 20; a light chain CDR2 that is a CDR2 in SEQ ID NO: 20; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 20,

d) an antibody comprising a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 5; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 5; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 5; and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 21; a light chain CDR2 that is a CDR2 in SEQ ID NO: 21; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 21,

e) an antibody comprising a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 7; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 7; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 7; and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 23; a light chain CDR2 that is a CDR2 in SEQ ID NO: 23; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 23,

f) an antibody comprising a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 9; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 9; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 9; and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 26; a light chain CDR2 that is a CDR2 in SEQ ID NO: 26; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 26,

g) an antibody comprising a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 10; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 10; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 10; and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 25; a light chain CDR2 that is a CDR2 in SEQ ID NO: 25; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 25,

h) an antibody comprising a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 12; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 12; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 12; and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 28; a light chain CDR2 that is a CDR2 in SEQ ID NO: 28; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 28,

i) an antibody comprising a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 13; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 13; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 13; and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 29; a light chain CDR2 that is a CDR2 in SEQ ID NO: 29; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 29,

j) an antibody comprising a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 15; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 15; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 15; and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 33; a light chain CDR2 that is a CDR2 in SEQ ID NO: 33; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 33,

k) an antibody comprising a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 16; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 16; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 16; and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 31; a light chain CDR2 that is a CDR2 in SEQ ID NO: 31; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 31, or

l) an antibody comprising a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 17; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 17; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 17; and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 32; a light chain CDR2 that is a CDR2 in SEQ ID NO: 32; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 32.

2. The method of claim 1 , wherein the toxin comprises the Maytansinoid.

3. The method of claim 1 , wherein the toxin comprises saporin.

4. The method of claim 2 , wherein the Maytansinoid comprises DM-1.

5. The method of claim 1 , wherein any one of the antibodies has a binding affinity greater than 1.3×10 −9 M to the peptide sequence of LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII.

6. The method of claim 1 , wherein the antibody conjugated to the toxin is at least 10 fold more toxic to targeted cells than to cells without the peptide sequence of LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII.

7. The method of claim 1 , wherein the antibody comprises a heavy chain variable region amino acid sequence selected from the group consisting of the heavy chain variable region of: SEQ ID NO: 142, SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17.

8. The method of claim 1 , wherein the antibody is conjugated to the toxin via a peptide linker.

9. The method of claim 1 , wherein the antibody is conjugated to the toxin via a second antibody.

10. A method of inhibiting cell proliferation associated with the expression of EGFRvIII, wherein the EGFRvIII comprises the amino acid sequence of SEQ ID NO: 56, said method comprising contacting the cell expressing the EGFRvIII with an effective amount of an antibody, that binds to LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII, wherein said antibody is conjugated to a toxin selected from a Maytansinoid and saporin, and wherein the antibody is

a) an antibody comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 142 and a light chain variable region amino acid sequence of SEQ ID NO: 144,

b) an antibody comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 2 and a light chain variable region amino acid sequence of SEQ ID NO: 19,

c) an antibody comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 4 and a light chain variable region amino acid sequence of SEQ ID NO: 20,

d) an antibody comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 5 and a light chain variable region amino acid sequence of SEQ ID NO: 21,

e) an antibody comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 7 and a light chain variable region amino acid sequence of SEQ ID NO: 23,

f) an antibody comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 9 and a light chain variable region amino acid sequence of SEQ ID NO: 26,

g) an antibody comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 10 and a light chain variable region amino acid sequence of SEQ ID NO: 25,

h) an antibody comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 12 and a light chain variable region amino acid sequence of SEQ ID NO: 28,

i) an antibody comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 13 and a light chain variable region amino acid sequence of SEQ ID NO: 29,

j) an antibody comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 15 and a light chain variable region amino acid sequence of SEQ ID NO: 33,

k) an antibody comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 16 and a light chain variable region amino acid sequence of SEQ ID NO: 31, or

l) an antibody comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 17 and a light chain variable region amino acid sequence of SEQ ID NO: 32.

11. The method of claim 10 , wherein the method is performed in vivo.

12. The method claim 10 , wherein the method is performed on a mammal.

13. The method of claim 12 , wherein the mammal is a human.

14. The method of claim 12 , wherein the mammal suffers from a cancer involving epithelial cell proliferation associated with the expression of EGFRvIII.

15. The method of claim 14 , wherein the cancer comprises a lung, colon, gastric, renal, prostate, breast, glioblastoma or ovarian carcinoma.

16. The method of claim 10 , wherein the toxin comprises the Maytansinoid.

17. The method of claim 10 , wherein the toxin comprises saporin.

18. The method of claim 16 , wherein the Maytansinoid comprises DM-1.

19. The method of claim 1 , wherein the heavy chain CDR1 is a CDR1 in SEQ ID NO: 2; wherein the heavy chain CDR2 is a CDR2 in SEQ ID NO: 2; wherein the heavy chain CDR3 is a CDR3 in SEQ ID NO: 2, wherein the light chain CDR1 is a CDR1 in SEQ ID NO: 19, wherein the light chain CDR2 is a CDR2 in SEQ ID NO: 19; and wherein the light chain CDR3 is a CDR3 in SEQ ID NO: 19.

20. The method of claim 1 , wherein the heavy chain polypeptide comprises SEQ ID NO: 108, SEQ ID NO: 110, and SEQ ID NO: 112.

21. The method of claim 1 wherein the light chain polypeptide comprises SEQ ID NO: 101, SEQ ID NO: 103, and SEQ ID NO: 105.

22. The method of claim 21 , wherein the heavy chain polypeptide comprises SEQ ID NO: 108, SEQ ID NO: 110, and SEQ ID NO: 112.

23. The method of claim 1 , wherein CDR3 of the heavy chain polypeptide comprises the amino acid sequence in SEQ ID NO: 112, wherein CDR2 of the heavy chain polypeptide comprises the amino acid sequence in SEQ ID NO: 110, and wherein CDR1 of the heavy chain polypeptide comprises the amino acid sequence in SEQ ID NO: 108, wherein CDR3 of the light chain polypeptide comprises the amino acid sequence in SEQ ID NO: 105, wherein CDR2 of the light chain polypeptide comprises the amino acid sequence in SEQ ID NO: 103, and wherein CDR1 of the light chain polypeptide comprises the amino acid sequence in SEQ ID NO: 101.

24. The method of claim 10 , wherein the antibody has a binding affinity greater than 1.3×10 −9 M to the peptide sequence of LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII.

25. The method of claim 10 , wherein the antibody conjugated to the toxin is at least 10 fold more toxic to targeted cells than to cells without the peptide sequence of LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII.

26. The method of claim 10 , wherein the antibody is conjugated to the toxin via a peptide linker.

27. The method of claim 10 , wherein the antibody is conjugated to the toxin via a second antibody.

28. The method of claim 10 , wherein the method is performed in vivo.

29. The method claim 10 , wherein the method is performed on a mammal.

30. The method of claim 29 , wherein the mammal is a human.

31. The method of claim 29 , wherein the mammal suffers from a cancer involving epithelial cell proliferation associated with the expression of EGFRvIII.

32. The method of claim 31 , wherein the cancer comprises a lung, colon, gastric, renal, prostate, breast, glioblastoma or ovarian carcinoma.

33. A method of inhibiting cell proliferation associated with the expression of EGFRvIII, wherein the EGFRvIII comprises the amino acid sequence of SEQ ID NO: 56, said method comprising contacting the cell expressing the EGFRvIII with an effective amount of an antibody that binds to LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII, wherein said antibody is conjugated to a toxin selected from a Maytansinoid and saporin, and wherein the antibody is

wherein each CDR is defined in accordance with the CDR definition of Kabat or Chothia.

34. The method of claim 33 , wherein the toxin comprises the Maytansinoid.

35. The method of claim 33 , wherein the toxin comprises saporin.

36. The method of claim 34 , wherein the Maytansinoid comprises DM-1.

37. The method of claim 33 , wherein any one of the antibodies has a binding affinity greater than 1.3×10 −9 M to the peptide sequence of LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII.

38. The method of claim 33 , wherein the antibody conjugated to the toxin is at least 10 fold more toxic to targeted cells than to cells without the peptide sequence of LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII.

39. The method of claim 33 , wherein the antibody comprises a heavy chain variable region amino acid sequence selected from the group consisting of the heavy chain variable region of: SEQ ID NO: 142, SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17.

40. The method of claim 33 , wherein the antibody comprises a light chain variable region amino acid sequence selected from the group consisting of the light chain variable region of: SEQ ID NO: 144, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 26, SEQ ID NO: 25, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 31, and SEQ ID NO: 32.

41. The method of claim 33 , wherein the antibody is conjugated to the toxin via a peptide linker.

42. The method of claim 33 , wherein the antibody is conjugated to the toxin via a second antibody.

43. The method of claim 33 , wherein the heavy chain CDR1 is a CDR1 in SEQ ID NO: 2, wherein the heavy chain CDR2 is a CDR2 in SEQ ID NO: 2, wherein the heavy chain CDR3 is a CDR3 in SEQ ID NO: 2, wherein the light chain CDR1 is a CDR1 in SEQ ID NO: 19, wherein the light chain CDR2 is a CDR2 in SEQ ID NO: 19, and wherein the light chain CDR3 is a CDR3 in SEQ ID NO: 19.

44. The method of claim 33 , wherein the heavy chain polypeptide comprises SEQ ID NO: 108, SEQ ID NO: 110, and SEQ ID NO: 112.

45. The method of claim 33 , wherein the light chain polypeptide comprises SEQ ID NO: 101, SEQ ID NO: 103, and SEQ ID NO: 105.

46. The method of claim 45 , wherein the heavy chain polypeptide comprises SEQ ID NO: 108, SEQ ID NO: 110, and SEQ ID NO: 112.

47. The method of claim 33 , wherein CDR3 of the heavy chain polypeptide comprises the amino acid sequence in SEQ ID NO: 112, wherein CDR2of the heavy chain polypeptide comprises the amino acid sequence in SEQ ID NO: 110, wherein CDR1 of the heavy chain polypeptide comprises the amino acid sequence in SEQ ID NO: 108, wherein CDR3 of the light chain polypeptide comprises the amino acid sequence in SEQ ID NO: 105, wherein CDR2 of the light chain polypeptide comprises the amino acid sequence in SEQ ID NO: 103, and wherein CDR1 of the light chain polypeptide comprises the amino acid sequence in SEQ ID NO: 101.

48. The method of claim 33 , wherein the heavy chain CDR1 is a CDR1 in SEQ ID NO: 142, wherein the heavy chain CDR2 is a CDR2 in SEQ ID NO: 142, wherein the heavy chain CDR3 is a CDR3 in SEQ ID NO: 142, wherein the light chain CDR1 is a CDR1 in SEQ ID NO: 144, wherein the light chain CDR2 is a CDR2 in SEQ ID NO: 144, and wherein the light chain CDR3 is a CDR3 in SEQ ID NO: 144.

49. The method of claim 33 , wherein the heavy chain polypeptide comprises SEQ ID NO: 121, SEQ ID NO: 123, and SEQ ID NO: 125.

50. The method of claim 49 , wherein the light chain polypeptide comprises SEQ ID NO: 101, SEQ ID NO: 116, and SEQ ID NO: 118.

51. The method of claim 33 , wherein the light chain polypeptide comprises SEQ ID NO: 101, SEQ ID NO: 116, and SEQ ID NO: 118.

52. The method of claim 33 , wherein CDR3 of the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 125, wherein CDR2of the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 123, wherein CDR1 of the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 121, wherein CDR3 of the light chain polypeptide comprises the amino acid sequence of SEQ ID NO: 118, wherein CDR2 of the light chain polypeptide comprises the amino acid sequence of SEQ ID NO: 116, and wherein CDR1 of the light chain polypeptide comprises the amino acid sequence of SEQ ID NO: 101.

53. The method of claim 1 , wherein the heavy chain CDR1 is a CDR1 in SEQ ID NO: 142, wherein the heavy chain CDR2 is a CDR2 in SEQ ID NO: 142, wherein the heavy chain CDR3 is a CDR3 in SEQ ID NO: 142, wherein the light chain CDR1 is a CDR1 in SEQ ID NO: 144, wherein the light chain CDR2 is a CDR2 in SEQ ID NO: 144, and wherein the light chain CDR3 is a CDR3 in SEQ ID NO: 144.

54. The method of claim 1 , wherein the heavy chain polypeptide comprises all three of the following amino acid sequences: SEQ ID NO: 121, SEQ ID NO: 123, and SEQ ID NO: 125.

55. The method of claim 1 , wherein the light chain polypeptide comprises all three of the following amino acid sequences: SEQ ID NO: 101, SEQ ID NO: 116, and SEQ ID NO: 118.

56. The method of claim 1 , wherein the light chain polypeptide comprises all three of the following amino acid sequences: SEQ ID NO: 101, SEQ ID NO: 116, and SEQ ID NO: 118.

57. The method of claim 1 , wherein CDR3 of the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 125, wherein CDR2 of the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 123, wherein CDR1of the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 121, wherein CDR3 of the light chain polypeptide comprises the amino acid sequence of SEQ ID NO: 118, wherein CDR2 of the light chain polypeptide comprises the amino acid sequence of SEQ ID NO: 116, and wherein CDR1 of the light chain polypeptide comprises the amino acid sequence of SEQ ID NO: 101.

58. A method of inhibiting cell proliferation associated with the expression of EGFRvIII, wherein the EGFRvIII comprises the amino acid sequence of SEQ ID NO: 56, said method comprising contacting the cell expressing the EGFRvIII with an effective amount of an antibody that binds to LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII, wherein said antibody is conjugated to a Maytansinoid toxin, and wherein the antibody comprises:

a heavy chain polypeptide, wherein CDR3 of the heavy chain polypeptide comprises the amino acid sequence in SEQ ID NO: 112, wherein CDR2 of the heavy chain polypeptide comprises the amino acid sequence in SEQ ID NO: 110, and wherein CDR1 of the heavy chain polypeptide comprises the amino acid sequence in SEQ ID NO: 108; and

a light chain polypeptide, wherein CDR3 of the light chain polypeptide comprises the amino acid sequence in SEQ ID NO: 105, wherein CDR2 of the light chain polypeptide comprises the amino acid sequence in SEQ ID NO: 103, and wherein CDR1 of the light chain polypeptide comprises the amino acid sequence in SEQ ID NO: 101.

59. A method of inhibiting cell proliferation associated with the expression of EGFRvIII, wherein the EGFRvIII comprises the amino acid sequence of SEQ ID NO: 56, said method comprising contacting the cell expressing the EGFRvIII with an effective amount of an antibody that binds to LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII, wherein said antibody is conjugated to a Maytansinoid toxin, and wherein the antibody comprises:

a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 2; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 2; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 2; and

a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 19; a light chain CDR2 that is a CDR2 in SEQ ID NO: 19; and

a light chain CDR3 that is a CDR3 in SEQ ID NO: 19,

wherein each CDR is defined in accordance with the CDR definition of Kabat or Chothia.

60. A method of inhibiting cell proliferation associated with the expression of EGFRvIII, wherein the EGFRvIII comprises the amino acid sequence of SEQ ID NO: 56, said method comprising contacting the cell expressing the EGFRvIII with an effective amount of an antibody that binds to LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII, wherein said antibody is conjugated to a Maytansinoid toxin, and wherein the antibody comprises:

a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 19; a light chain CDR2 that is a CDR2 in SEQ ID NO: 19; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 19.

61. The method of claim 60 , wherein the heavy chain polypeptide comprises all three of the following amino acid sequences: SEQ ID NO: 108, SEQ ID NO: 110, and SEQ ID NO: 112.

62. The method of claim 61 , wherein the light chain polypeptide comprises all three of the following sequences: SEQ ID NO: 101, SEQ ID NO: 103, and SEQ ID NO: 105.

63. The method of claim 62 , wherein the antibody has a binding affinity greater than 1.3×10 −9 M to the peptide sequence of LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII.

64. The method of claim 62 , wherein the antibody conjugated to the toxin is at least 10 fold more toxic to targeted cells than to cells without the peptide sequence of LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII.

65. The method of claim 62 , wherein the method is performed in vivo.

66. The method claim 62 , wherein the method is performed on a mammal.

67. The method of claim 66 , wherein the mammal is a human.

68. The method of claim 66 , wherein the mammal suffers from a cancer involving epithelial cell proliferation associated with the expression of EGFRvIII.

69. The method of claim 68 , wherein the cancer comprises a lung, colon, gastric, renal, prostate, breast, glioblastoma or ovarian carcinoma.

70. The method of claim 1 , wherein the antibody comprises a light chain variable region amino acid sequence selected from the group consisting of the light chain variable region of: SEQ ID NO: 144, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 26, SEQ ID NO: 25, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 31, and SEQ ID NO: 32.

71. A method of inhibiting cell proliferation associated with the expression of EGFRvIII, wherein the EGFRvIII comprises the amino acid sequence of SEQ ID NO: 56, said method comprising contacting the cell expressing the EGFRvIII with an effective amount of an antibody that binds to LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII, wherein said antibody is conjugated to a Maytansinoid toxin, and wherein the antibody comprises:

a heavy chain polypeptide, wherein CDR3 of the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 125, wherein CDR2 of the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 123, and wherein CDR1 of the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 121; and

a light chain polypeptide, wherein CDR3 of the light chain polypeptide comprises the amino acid sequence of SEQ ID NO: 118, wherein CDR2 of the light chain polypeptide comprises the amino acid sequence of SEQ ID NO: 116, and wherein CDR1of the light chain polypeptide comprises the amino acid sequence of SEQ ID NO: 101.

72. A method of inhibiting cell proliferation associated with the expression of EGFRvIII, wherein the EGFRvIII comprises the amino acid sequence of SEQ ID NO: 56, said method comprising contacting the cell expressing the EGFRvIII with an effective amount of an antibody that binds to LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII, wherein said antibody is conjugated to a Maytansinoid toxin, and wherein the antibody comprises:

a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 142; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 142; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 142; and

a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 144; a light chain CDR2 that a CDR2 in SEQ ID NO: 144; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 144,

wherein each CDR is defined in accordance with the CDR definition of Kabat or Chothia.

73. A method of inhibiting cell proliferation associated with the expression of EGFRvIII, wherein the EGFRvIII comprises the amino acid sequence of SEQ ID NO: 56, said method comprising contacting the cell expressing the EGFRvIII with an effective amount of an antibody that binds to LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII, wherein said antibody is conjugated to a Maytansinoid toxin, and wherein the antibody comprises:

74. The method of claim 73 , wherein the heavy chain polypeptide comprises all three of the following amino acid sequences: SEQ ID NO: 121, SEQ ID NO: 123, and SEQ ID NO: 125.

75. The method of claim 74 , wherein the light chain polypeptide comprises all three of the following amino acid sequences: SEQ ID NO: 101, SEQ ID NO: 116, and SEQ ID NO: 118.

76. sly presented) The method of claim 75 , wherein the antibody has a binding affinity greater than 1.3×10 −9 M to the peptide sequence of LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII.

77. The method of claim 75 , wherein the antibody conjugated to the toxin is at least 10 fold more toxic to targeted cells than to cells without the peptide sequence of LEEKKGNYVVTDHC (SEQ ID NO: 56) of EGFRvIII.

78. The method of claim 75 , wherein the method is performed in vivo.

79. The method claim 75 , wherein the method is performed on a mammal.

80. The method of claim 79 , wherein the mammal is a human.

81. The method of claim 79 , wherein the mammal suffers from a cancer involving epithelial cell proliferation associated with the expression of EGFRvIII.

82. The method of claim 81 , wherein the cancer comprises a lung, colon, gastric, renal, prostate, breast, glioblastoma or ovarian carcinoma.

83. The method of claim 58 , wherein the Maytansinoid comprises DM-1.

84. The method of claim 59 , wherein the Maytansinoid comprises DM-1.

85. The method of claim 60 , wherein the Maytansinoid comprises DM-1.

86. The method of claim 71 , wherein the Maytansinoid comprises DM-1.

87. The method of claim 72 , wherein the Maytansinoid comprises DM-1.

88. The method of claim 73 , wherein the Maytansinoid comprises DM-1.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 28, 2014

From: WEBER, RICHARD; FENG, XIAO; FOORD, ORIT; GREEN, LARRY; KEYT, BRUCE; GUDAS, JEAN M.; LIU, YING; RATHANASWAMI, PALANISWAMI; RAYA, ROBERT; YANG, XIAO DONG; FOLTZ, IAN; CORVALAN, JOSE; JIA, XIAO-CHI; KANG, JASPAL; KING, CHADWICK T.; KLAKAMP, SCOTT L.; SU, QIAOJUAN JANE

To: ABGENIX, INC.

Reel/Frame 032551/0801 →

CHANGE OF NAME Recorded Mar 28, 2014

From: ABGENIX, INC.

To: AMGEN FREMONT INC.

Reel/Frame 032552/0825 →

Continuity (5)

Division 10877773 · Jun 25, 2004

Provisional Application 60483145 · Jun 27, 2003

Provisional Application 60525570 · Nov 26, 2003

Provisional Application 60562453 · Apr 15, 2004

Related Publication 20090175887A1 · Jul 9, 2009