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Last Updated: March 29, 2024

Claims for Patent: 8,663,640


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Summary for Patent: 8,663,640
Title:Methods using recombinant anti-epidermal growth factor receptor antibody compositions
Abstract: The invention relates to the field of recombinant antibodies for use in human cancer therapy. More specifically the invention provides the use of an antibody composition with two distinct non-overlapping binding specificities to human EGFR. The antibody composition is effecting in treating cancer following treatment with other anti-EGFR antibodies, whether the cancer shows progression during or following the prior treatment or not. The antibody composition can also be used for repeated treatment of recurrent tumors following first-line therapy with the antibody composition of the invention, as the composition does not lead to selection of resistant tumors. A further therapeutic use is the use of an antibody composition of the invention for treatment of cancer that is resistant to known anti-EGFR antibodies.
Inventor(s): Pedersen; Mikkel Wandahl (Alleroed, DK), Kragh; Michael (Copenhagen, DK), Hey; Adam S. (Vanloese, DK), Jacobsen; Helle (Virum, DK)
Assignee: Symphogen A/S (Lyngby, DK)
Application Number:13/061,417
Patent Claims:1. A method for treatment of cancer in a subject in need thereof that has been subjected to a prior treatment regimen using an anti-human EGFR antibody, said method comprising administering to said subject an antibody composition comprising at least a first anti-human EGFR antibody molecule and a second anti-human EGFR antibody molecule distinct from the first molecule, a. wherein the first anti-human EGFR antibody molecule is selected from the group consisting, (i) an antibody whose light chain comprises amino acids 3-216 of SEQ ID NO:72, and whose heavy chain has a variable domain (VH) comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose light chain has a variable domain (VL) comprising amino acids 3-109 of SEQ ID NO:72 and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 72 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 40; and b. wherein the second anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-221 of SEQ ID NO:73, and whose heavy chain has a variable domain (VH) comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91: (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 73 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 41, wherein the prior treatment regimen does not use the first antibody molecule, the second antibody molecule, an antibody molecule have light chain CDR1, CDR2 and CDR3 in SEQ ID NO:74 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO:42, or any combination of these antibody molecules.

2. The method of claim 1, wherein said prior treatment regimen used an anti-human EGFR antibody selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as cetuximab, panitumumab, or zalutumumab.

3. The method of claim 2, wherein said anti-human EGFR antibody is selected from the group consisting of cetuximab, panitumumab, zalutumumab, and antibodies capable of binding the same epitope as any of these.

4. The method of claim 2, wherein said anti-human EGFR antibody is selected from the group consisting of cetuximab, panitumumab, and antibodies capable of binding the same epitope as either of these.

5. The method of claim 2, wherein said anti-human EGFR antibody is cetuximab or an antibody capable of binding the same epitope as cetuximab.

6. The method of claim 1, wherein said cancer is selected from the group consisting of head-and-neck cancer, colon cancer, breast cancer, renal cancer, lung cancer, ovarian cancer, prostate cancer, glioma, pancreatic cancer, bladder cancer, non-small-cell-lung-carcinoma (NSCLC), gastric cancer, cervical cancer, hepatocellular cancer, gastrophageal cancer, colorectal cancer, rectal cancer, epithelioid carcinoma, RCC, squamous cell carcinoma of the head and neck (SCCHN), esophageal cancer, glioblastoma multiforme, squamous cell carcinoma, kidney cancer, sarcoma, and melanoma.

7. The method of claim 1, wherein said composition is used as adjuvant therapy following surgery and/or radiation therapy.

8. The method of claim 1, wherein said composition is used for combination therapy together with (a) chemotherapy, (b) at least one tyrosine kinase inhibitor, (c) at least one angiogenesis inhibitor, (d) at least one hormone, (e) at least one differentiation inducing agent, or (f) any combination of (a)-(e).

9. The method of claim 1, wherein said prior treatment regimen was first-line therapy.

10. The method of claim 1, wherein said prior treatment regimen was second-line therapy.

11. The method of claim 10, wherein the second-line therapy comprised a treatment regimen with (a) chemotherapy, (b) at least one tyrosine kinase inhibitor, (c) at least one angiogenesis inhibitor, (d) at least one hormone, (e) at least one differentiation inducing agent, or (f) any combination of (a)-(e).

12. The method of claim 8 or 11, wherein the chemotherapy comprises administration of a compound selected from the group consisting of adriamycin, cisplatin, taxol, doxorubicin, topotecan, fluoropyrimidine, oxaliplatin, and irinotecan.

13. The method of claim 1, wherein the cancer of said subject had progressed during said prior treatment regimen.

14. The method of claim 1, wherein the cancer of said subject had progressed following said prior treatment regimen.

15. The method of claim 1, wherein said cancer was resistant or partially resistant to said prior treatment regimen.

16. The method of claim 1, wherein a. said first anti-human EGFR antibody molecule comprises a light chain comprising amino acids 3-216 of SEQ ID NO:72, and a heavy chain that has a VH comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; and b. said second anti-human EGFR antibody molecule comprises a light chain comprising amino acids 3-221 of SEQ ID NO:73, and a heavy chain that has a VH comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91.

17. The method of claim 1, wherein a. the first anti-human EGFR antibody molecule whose VL comprises amino acids 3-109 of SEQ ID NO:72, and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and b. the second anti-human EGFR antibody molecule whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41.

18. The method of claim 1, wherein the first and second anti-human EGFR antibody molecules of said composition do not inhibit the binding to human EGFR of each other.

19. The method of claim 1, wherein at least one of the antibody molecules of said composition is capable of increasing the maximum binding capacity of the other antibody molecule with respect to human EGFR.

20. The method of claim 1, wherein the proportion of the first antibody molecule relative to the second antibody molecule in the composition is between 5 and 95%.

21. The method of claim 1, wherein the first and second antibody molecules of the composition are of isotype IgG1 or IgG2.

22. The method of claim 1, wherein the composition does not contain further anti-EGFR antibody molecules in addition to said first and second antibody molecules.

23. The method of claim 1, wherein the composition further comprises a third distinct anti-EGFR antibody molecule, wherein said third distinct anti-EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-220 of SEQ ID NO:74, and whose heavy chain has a VH comprising amino acids 3-120 of SEQ ID NO:42 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:74 and whose VH comprises amino acids 3-120 of SEQ ID NO:42; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 74 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 42.

24. The method of claim 23, wherein said third antibody molecule results in an enhanced binding to human EGFR of said first and/or second antibody molecule.

25. The method of claim 23, wherein the composition does not contain further anti-EGFR antibody molecules in addition to said first, second, and third antibody molecules.

26. The method of claim 1, wherein the distinct antibody molecules of the composition are prepared for simultaneous, successive or separate administration.

27. The method of claim 1, wherein the composition leads to receptor internalisation.

28. The method of claim 1, wherein the composition leads to regression of A431NS tumours in vivo.

29. The method of claim 1, wherein the composition induces terminal differentiation in A431NS cells in vivo.

30. The method of claim 1, wherein the composition up-regulates tumour involucrin expression in vivo.

31. The method of claim 1, wherein the first and second anti-EGFR antibody molecules form part of a bi-specific binding molecule.

32. The method of claim 31, wherein the bi-specific binding molecule comprises the light chain CDR1, CDR2, and CDR3 in SEQ ID NOs: 72 and 73 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NOs: 40 and 41.

33. The method of claim 31, wherein the bi-specific binding molecule is a dual-variable-domain antibody.

34. The method of claim 31, wherein the bi-specific binding molecule is a bi-specific Fab-fragment or a bi-specific scFv.

35. The method of claim 1, wherein the ratio of the first antibody molecule to the second antibody molecule is 1:1.

36. A method for treatment of cancer in a subject in need thereof, comprising administering to said subject an antibody composition comprising at least a first anti-human EGFR antibody molecule and a second anti-human EGFR antibody molecule distinct from the first molecule, a. wherein the first anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-216 of SEQ ID NO:72, and whose heavy chain has a variable domain (VH) comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-109 of SEQ ID NO:72 and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 72 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 40; and b. wherein the second anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-221 of SEQ ID NO:73, and whose heavy chain has a variable domain (VH) comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 73 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 41, wherein said cancer is resistant or partially resistant to treatment with at least one other anti-EGFR antibody selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as cetuximab, panitumumab, or zalutumumab.

37. The method of claim 36, wherein a. said first anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-216 of SEQ ID NO:72, and whose heavy chain has a variable domain (VH) comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; and (ii) an antibody whose VL comprises amino acids 3-109 of SEQ ID NO:72 and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and b. said second anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-221 of SEQ ID NO:73, and whose heavy chain has a variable domain (VH) comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; and (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41.

38. The method of claim 36, wherein said composition is used for first-line therapy.

39. The method of claim 36, wherein said composition is used for second-line therapy following a treatment regimen with (a) chemotherapy, (b) at least one tyrosine kinase inhibitor, (c) at least one angiogenesis inhibitor, (d) at least one hormone, (e) at least one differentiation inducing agent, or (f) any combination of (a)-(e).

40. The method of claim 36, wherein said composition is used for third-line therapy.

41. The method of claim 36, wherein said composition is used for combination therapy together with (a) chemotherapy, (b) at least one tyrosine kinase inhibitor, (c) at least one angiogenesis inhibitor, (d) at least one hormone, (e) at least one differentiation inducing agent, or (f) any combination of (a)-(e).

42. The method of claim 36, wherein said composition is used as adjuvant therapy following surgery and/or radiation therapy.

43. The method of claim 36, wherein the resistance or partial resistance has been determined by assaying a sample of cancer cells isolated from said subject.

44. A method of reducing EGFR signalling comprising administering an antibody composition to a composition of EGFR expressing cells, said cells having previously been subjected to an anti-human EGFR antibody selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as cetuximab, panitumumab, or zalutumumab, wherein said antibody composition comprises at least a first anti-human EGFR antibody molecule and a second anti-human EGFR antibody molecule distinct from the first molecule, a. wherein the first anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-216 of SEQ ID NO:72, and whose heavy chain has a variable domain (VH) comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-109 of SEQ ID NO:72 and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 72 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 40; and b. wherein the second anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-221 of SEQ ID NO:73, and whose heavy chain has a variable domain (VH) comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 73 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 41, whereby the EGFR signalling is reduced.

45. A method of killing cells expressing EGFR comprising administering an antibody composition to EGFR expressing cells, said cells having previously been subjected to an anti-human EGFR antibody selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as cetuximab, panitumumab, or zalutumumab, wherein said antibody composition comprises at least a first anti-human EGFR antibody molecule and a second anti-human EGFR antibody molecule distinct from the first molecule, a. wherein the first anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-216 of SEQ ID NO:72, and whose heavy chain has a variable domain (VH) comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-109 of SEQ ID NO:72 and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 72 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 40; and b. wherein the second anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-221 of SEQ ID NO:73, and whose heavy chain has a variable domain (VH) comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 73 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 41, wherein the EGFR expressing cells are killed.

46. A method of inducing apoptosis in cells expressing EGFR, comprising administering an antibody composition to EGFR expressing cells, said cells having previously been subjected to an anti-human EGFR antibody selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as cetuximab, panitumumab, or zalutumumab, wherein said antibody composition comprises at least a first anti-human EGFR antibody molecule and a second anti-human EGFR antibody molecule distinct from the first molecule, a. wherein the first anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-216 of SEQ ID NO:72, and whose heavy chain has a variable domain (VH) comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-109 of SEQ ID NO:72 and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 72 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 40; and b. wherein the second anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-221 of SEQ ID NO:73, and whose heavy chain has a variable domain (VH) comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 73 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 41, thereby inducing apoptosis.

47. A method of inhibiting proliferation of cells expressing EGFR comprising administering an antibody composition to EGFR expressing cells, said cells having previously been subjected to an anti-human EGFR antibody selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as cetuximab, panitumumab, or zalutumumab, wherein said antibody composition comprises at least a first anti-human EGFR antibody molecule and a second anti-human EGFR antibody molecule distinct from the first molecule, a. wherein the first anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-216 of SEQ ID NO:72, and whose heavy chain has a variable domain (VH) comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-109 of SEQ ID NO:72 and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 72 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 40; and b. wherein the second anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-221 of SEQ ID NO:73, and whose heavy chain has a variable domain (VH) comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 73 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 41, thereby inhibiting proliferation.

48. A method of inducing differentiation of tumour cells in vivo, comprising administering an antibody composition to EGFR expressing tumour cells, said cells having previously been subjected to an anti-human EGFR antibody selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as cetuximab, panitumumab, or zalutumumab, wherein said antibody composition comprises at least a first anti-human EGFR antibody molecule and a second anti-human EGFR antibody molecule distinct from the first molecule, a. wherein the first anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-216 of SEQ ID NO:72, and whose heavy chain has a variable domain (VH) comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-109 of SEQ ID NO:72 and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 72 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 40; and b. wherein the second anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-221 of SEQ ID NO:73, and whose heavy chain has a variable domain (VH) comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 73 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 41, thereby inducing differentiation of the tumour cells.

49. The method of claim 48, wherein said differentiation is terminal.

50. The method of claim 48, wherein said differentiation is accompanied by an increase in involucrin expression.

51. A method for inducing internalisation of EGFR comprising administering an antibody composition to EGFR expressing cells, said cells having previously been subjected to an anti-human EGFR antibody selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as cetuximab, panitumumab, or zalutumumab, wherein said antibody composition comprises at least a first anti-human EGFR antibody molecule and a second anti-human EGFR antibody molecule distinct from the first molecule, a. wherein the first anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-216 of SEQ ID NO:72, and whose heavy chain has a variable domain (VH) comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-109 of SEQ ID NO:72 and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 72 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 40; and b. wherein the second anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-221 of SEQ ID NO:73, and whose heavy chain has a variable domain (VH) comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 73 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 41, thereby inducing internalisation of EGFR.

52. A method of reducing EGFR signalling comprising administering an antibody composition to EGFR expressing cells, said cells being resistant or partially resistant to an anti-human EGFR antibody selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as cetuximab, panitumumab, or zalutumumab, wherein said antibody composition comprises at least a first anti-human EGFR antibody molecule and a second anti-human EGFR antibody molecule distinct from the first molecule, a. wherein the first anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-216 of SEQ ID NO:72, and whose heavy chain has a variable domain (VH) comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-109 of SEQ ID NO:72 and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 72 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 40; and b. wherein the second anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-221 of SEQ ID NO:73, and whose heavy chain has a variable domain (VH) comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 73 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 41, whereby the EGFR signalling is reduced.

53. A method of killing cells expressing EGFR comprising administering an antibody composition to EGFR expressing cells, said cells being resistant or partially resistant to an anti-human EGFR antibody selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as cetuximab, panitumumab, or zalutumumab, wherein said antibody composition comprises at least a first anti-human EGFR antibody molecule and a second anti-human EGFR antibody molecule distinct from the first molecule, a. wherein the first anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-216 of SEQ ID NO:72, and whose heavy chain has a variable domain (VH) comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-109 of SEQ ID NO:72 and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 72 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 40; and b. wherein the second anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-221 of SEQ ID NO:73, and whose heavy chain has a variable domain (VH) comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 73 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 41, wherein the EGFR expressing cells are killed.

54. A method of inducing apoptosis in cells expressing EGFR, comprising administering an antibody composition to EGFR expressing cells, said cells being resistant or partially resistant to an anti-human EGFR antibody selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as cetuximab, panitumumab, or zalutumumab, wherein said antibody composition comprises at least a first anti-human EGFR antibody molecule and a second anti-human EGFR antibody molecule distinct from the first molecule, a. wherein the first anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-216 of SEQ ID NO:72, and whose heavy chain has a variable domain (VH) comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-109 of SEQ ID NO:72 and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 72 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 40; and b. wherein the second anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-221 of SEQ ID NO:73, and whose heavy chain has a variable domain (VH) comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 73 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 41, thereby inducing apoptosis.

55. A method of inhibiting proliferation of cells expressing EGFR comprising administering an antibody composition to EGFR expressing cells, said cells being resistant or partially resistant to an anti-human EGFR antibody selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as cetuximab, panitumumab, or zalutumumab, wherein said antibody composition comprises at least a first anti-human EGFR antibody molecule and a second anti-human EGFR antibody molecule distinct from the first molecule, a. wherein the first anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-216 of SEQ ID NO:72, and whose heavy chain has a variable domain (VH) comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-109 of SEQ ID NO:72 and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 72 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 40; and b. wherein the second anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-221 of SEQ ID NO:73, and whose heavy chain has a variable domain (VH) comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 73 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 41, thereby inhibiting proliferation.

56. A method of inducing differentiation of tumour cells in vivo, comprising administering an antibody composition to EGFR expressing tumour cells, said cells being resistant or partially resistant to an anti-human EGFR antibody selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as cetuximab, panitumumab, or zalutumumab, any of these, wherein said antibody composition comprises at least a first anti-human EGFR antibody molecule and a second anti-human EGFR antibody molecule distinct from the first molecule, a. wherein the first anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-216 of SEQ ID NO:72, and whose heavy chain has a variable domain (VH) comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-109 of SEQ ID NO:72 and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 72 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 40; and b. wherein the second anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-221 of SEQ ID NO:73, and whose heavy chain has a variable domain (VH) comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 73 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 41, thereby inducing differentiation of the tumour cells.

57. The method of claim 56, wherein said differentiation is terminal.

58. The method of claim 56, wherein said differentiation is accompanied by an increase in involucrin expression.

59. A method for inducing internalisation of EGFR comprising administering an antibody composition to EGFR expressing cells, said cells being resistant or partially resistant to an anti-human EGFR antibody selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as cetuximab, panitumumab, or zalutumumab, any of these, wherein said antibody composition comprises at least a first anti-human EGFR antibody molecule and a second anti-human EGFR antibody molecule distinct from the first molecule, a. wherein the first anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-216 of SEQ ID NO:72, and whose heavy chain has a variable domain (VH) comprising amino acids 3-124 of SEQ ID NO:40 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-109 of SEQ ID NO:72 and whose VH comprises amino acids 3-124 of SEQ ID NO:40; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 72 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 40; and b. wherein the second anti-human EGFR antibody molecule is selected from the group consisting of (i) an antibody whose light chain comprises amino acids 3-221 of SEQ ID NO:73, and whose heavy chain has a variable domain (VH) comprising amino acids 3-120 of SEQ ID NO:41 and a constant region comprising the amino acid sequence of SEQ ID NO: 91; (ii) an antibody whose VL comprises amino acids 3-114 of SEQ ID NO:73 and whose VH comprises amino acids 3-120 of SEQ ID NO:41; and (iii) an antibody having the light chain CDR1, CDR2, and CDR3 in SEQ ID NO: 73 and the heavy chain CDR1, CDR2, and CDR3 in SEQ ID NO: 41, thereby inducing internalisation of EGFR.

Details for Patent 8,663,640

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Eli Lilly And Company ERBITUX cetuximab Injection 125084 02/12/2004 ⤷  Try a Trial 2028-08-29
Eli Lilly And Company ERBITUX cetuximab Injection 125084 03/28/2007 ⤷  Try a Trial 2028-08-29
Amgen, Inc. VECTIBIX panitumumab Injection 125147 09/27/2006 ⤷  Try a Trial 2028-08-29
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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