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1. (WO2019043059) COMPOSITIONS ET PROCÉDÉS POUR LE TRAITEMENT DU CANCER PAR DES ANTICORPS ANTI-EGFR
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CLAIMS

1 . A method for treating cancer in a patient, comprising:

a) selecting a patient with said cancer from whom a tumor DNA sample: i) has a mutant allele frequency (MAF) of less than 20% for (1 ) mutations in KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146);

ii) has a MAF of less than 0.1 % for BRAF mutation V600E; and iii) has a MAF of less than 0.1 % for EGFR ECD mutations V441 D, V441 G, S464L, G465E, G465R, and S492R, and

b) administering to the patient an anti-EGFR antibody composition

comprising two anti-human EGFR antibodies that bind to distinct epitopes in the EGFR extracellular domain (ECD).

2. A method for treating cancer in a patient, comprising:

a) selecting a patient with said cancer from whom a tumor DNA sample: i) has a mutant allele frequency (MAF) of less than 20% for (1 ) mutations in KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and

ii) has a MAF of less than 0.1 % for BRAF mutation V600E, and b) administering to the patient an anti-EGFR antibody composition

comprising two anti-human EGFR antibodies that bind to distinct epitopes in the EGFR extracellular domain (ECD).

3. The method of claim 1 , wherein the tumor DNA sample has no detectable levels of EGFR ECD mutations V441 D, V441 G, S464L, G465E, G465R, and S492R.

4. The method of any one of claims 1 -3, wherein the tumor DNA sample has no detectable levels of BRAF mutation V600E.

5. The method of any one of claims 1 -4, wherein the tumor DNA sample has been determined to be also negative for gene amplification of MET and ERBB2.

6. The method of claim 5, wherein the tumor DNA sample has been determined to be also negative for gene amplification of KRAS.

7. The method of any one of claims 1 -6, wherein the cancer is selected from the group consisting of colorectal cancer, non-small cell lung cancer (NSCLC), and squamous cell carcinoma of the head and neck (SCCHN).

8. The method of claim 7, wherein the cancer is colorectal cancer.

9. The method of claim 8, wherein the cancer is metastatic colorectal cancer.

10. The method of any one of claims 1 -9, wherein the patient has received prior treatment with an anti-EGFR antibody that is not an antibody in said antibody composition.

1 1 . The method of claim 10, wherein the prior anti-EGFR antibody is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as any of these.

12. The method of claim 10, wherein the patient has been treated with cetuximab, panitumumab, or both.

13. The method of any one of claims 1 -12, wherein said cancer is resistant or partially resistant to prior treatment with an anti-EGFR antibody that is not an antibody in said antibody composition.

14. The method of claim 13, wherein the prior anti-EGFR antibody is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, ICR62, mAb806, matuzumab, and antibodies capable of binding the same epitope as any of these.

15. The method of claim 13, wherein said cancer is resistant or partially resistant to prior treatment with cetuximab, panitumumab, or both.

16. The method of any one of claims 13-15, wherein the resistance or partial resistance has been determined by assaying a sample of cancer cells isolated from said patient.

17. The method of any one of claims 1 -16, wherein the patient has demonstrated intolerance to, or failed on prior treatment with, at least one chemotherapy agent selected from the group consisting of 5-FU, oxaliplatin, irinotecan, FOLFOX (folinic acid, fluorouracil and oxaliplatin), and FOLFIRI (folinic acid, fluorouracil and irinotecan).

18. The method of any one of claims 1 -17, wherein the tumor DNA sample is a circulating tumor (ct) DNA sample from the patient.

19. The method of any one of claims 1 -17, wherein the tumor DNA sample is obtained from a tumor tissue sample or circulating tumor cells from the patient.

20. The method of any one of claims 1 -19, wherein the anti-EGFR antibody

composition has at least one of the following properties:

a) enhances internalization and degradation of EGFR;

b) induces complement-dependent cytotoxicity (CDC);

c) induces differentiation of tumor cells in vivo; and

d) increases involucrin expression in vivo.

21 . The method of claim 20, wherein the anti-EGFR antibody composition has all of said properties.

22. The method of any one of claims 1 -21 , wherein the anti-EGFR antibody

composition comprises a first anti-human EGFR antibody and a second anti- human EGFR antibody, wherein:

the first anti-human EGFR antibody comprises the heavy chain CDR1 , CDR2, and CDR3 in SEQ ID NO: 1 and the light chain CDR1 , CDR2, and CDR3 in SEQ ID NO: 2; and

the second anti-human EGFR antibody comprises the heavy chain CDR1 , CDR2, and CDR3 in SEQ ID NO: 3 and the light chain CDR1 , CDR2, and CDR3 in SEQ ID NO: 4.

23. The method of claim 22, wherein

the first anti-human EGFR antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 and a light chain comprising the amino acid sequence of SEQ ID NO: 2; and

the second anti-human EGFR antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3 and a light chain comprising the amino acid sequence of SEQ ID NO: 4.

24. The method of claim 23, wherein

the first anti-human EGFR antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 26 and a light chain comprising the amino acid sequence of SEQ ID NO: 24; and

the second anti-human EGFR antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain comprising the amino acid sequence of SEQ ID NO: 25.

25. The method of any one of claims 1 -23, wherein the first and second anti- human EGFR antibodies of the composition are of isotype lgG1 or lgG2.

26. The method of any one of claims 1 -25, wherein the ratio of the first anti- human EGFR antibody relative to the second anti-human EGFR antibody is 1 :1 .

27. The method of any one of claims 1 -26, wherein the antibody composition is administered to the patient at a loading dose of 9 mg/kg, followed by a weekly dose of 6 mg/kg.

28. The method of any one of claims 1 -26, wherein the antibody composition is administered to the patient at a weekly dose of 12 mg/kg.

29. The method of any one of claims 1 -28, wherein the patient is human.

30. A method for treating cancer in a human patient, comprising administering to the patient an anti-EGFR antibody composition comprising:

a first anti-human EGFR antibody that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 26 and a light chain comprising the amino acid sequence of SEQ ID NO: 24; and

a second anti-human EGFR antibody that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain comprising the amino acid sequence of SEQ ID NO: 25;

wherein the antibody composition is administered intravenously to the patient at a loading dose of 9 mg/kg, followed one week later by a weekly dose of 6 mg/kg.

31 . A method for treating cancer in a human patient, comprising:

a) selecting a patient with said cancer from whom a tumor DNA sample: i) has a mutant allele frequency (MAF) of less than 20% for (1 ) mutations in KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146),

ii) has a MAF of less than 0.1 % for BRAF mutation V600E, and

iii) has a MAF of less than 0.1 % for EGFR ECD mutations V441 D, V441 G, S464L, G465E, G465R, and S492R; and b) administering to the patient an anti-EGFR antibody composition

comprising:

a first anti-human EGFR antibody that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 26 and a light chain comprising the amino acid sequence of SEQ ID NO: 24; and a second anti-human EGFR antibody that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain comprising the amino acid sequence of SEQ ID NO: 25; wherein the antibody composition is administered intravenously to the patient at a loading dose of 9 mg/kg, followed one week later by a weekly dose of 6 mg/kg.

A method for treating cancer in a patient, comprising:

a) selecting a patient with said cancer from whom a tumor DNA sample: i) has a mutant allele frequency (MAF) of less than 20% for (1 ) mutations in KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146), and ii) has a MAF of less than 0.1 % for of BRAF mutation V600E; and b) administering to the patient an anti-EGFR antibody composition

comprising:

a first anti-human EGFR antibody that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 26 and a light chain comprising the amino acid sequence of SEQ ID NO: 24; and a second anti-human EGFR antibody that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain comprising the amino acid sequence of SEQ ID NO: 25; wherein the antibody composition is administered intravenously to the patient at a loading dose of 9 mg/kg, followed one week later by a weekly dose of 6 mg/kg.

33. The method of claim 31 , wherein the tumor DNA sample has no detectable levels of EGFR ECD mutations V441 D, V441 G, S464L, G465E, G465R, and S492R.

34. The method of any one of claims 31 -33, wherein the tumor DNA sample has no detectable levels of BRAF mutation V600E.

35. The method of any one of claims 30-34, wherein the patient has metastatic colorectal cancer.

36. Use of an antibody composition comprising two anti-human EGFR antibodies that bind to distinct epitopes in the EGFR extracellular domain (ECD) for the manufacture of a medicament for treating cancer in a patient, wherein a tumor DNA sample from the patient:

i) has a mutant allele frequency (MAF) of less than 20% for (1 ) mutations in KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146);

ii) has a MAF of less than 0.1 % for BRAF mutation V600E; and

iii) has a MAF of less than 0.1 % for EGFR ECD mutations V441 D, V441 G, S464L, G465E, G465R, and S492R.

37. Use of an antibody composition comprising two anti-human EGFR antibodies that bind to distinct epitopes in the EGFR extracellular domain (ECD) for the manufacture of a medicament for treating cancer in a patient, wherein a tumor DNA sample from the patient:

i) has a mutant allele frequency (MAF) of less than 20% for (1 ) mutations in KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and

ii) has a MAF of less than 0.1 % for BRAF mutation V600E.

38. The use of claim 36 or 37, wherein the medicament is for treating cancer in a patient in the method of any one of claims 1 -35.

39. An antibody composition comprising two anti-human EGFR antibodies that bind to distinct epitopes in the EGFR extracellular domain (ECD) for use in treating cancer in a patient in a method comprising:

a) selecting a patient with said cancer from whom a tumor DNA sample: i) has a mutant allele frequency (MAF) of less than 20% for (1 ) mutations in KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146);

ii) has a MAF of less than 0.1 % for BRAF mutation V600E; and iii) has a MAF of less than 0.1 % for EGFR ECD mutations V441 D, V441 G, S464L, G465E, G465R, and S492R, and

b) administering to the patient an anti-EGFR antibody composition

comprising two anti-human EGFR antibodies that bind to distinct epitopes in the EGFR extracellular domain (ECD).

40. An antibody composition comprising two anti-human EGFR antibodies that bind to distinct epitopes in the EGFR extracellular domain (ECD) for use in treating cancer in a patient in a method comprising:

a) selecting a patient with said cancer from whom a tumor DNA sample: i) has a mutant allele frequency (MAF) of less than 20% for (1 ) mutations in KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and

ii) has a MAF of less than 0.1 % for BRAF mutation V600E, and

b) administering to the patient an anti-EGFR antibody composition comprising two anti-human EGFR antibodies that bind to distinct epitopes in the EGFR extracellular domain (ECD).

41 . The antibody composition of claim 39 or 40, for use in treating cancer in a patient in the method of any one of claims 1 -35.

42. An article of manufacture suitable for treating cancer in a patient, comprising an antibody composition comprising two anti-human EGFR antibodies that bind to distinct epitopes in the EGFR extracellular domain (ECD), wherein said treatment comprises:

a) selecting a patient with said cancer from whom a tumor DNA sample: i) has a mutant allele frequency (MAF) of less than 20% for (1 ) mutations in KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146);

ii) has a MAF of less than 0.1 % for BRAF mutation V600E; and iii) has a MAF of less than 0.1 % for EGFR ECD mutations V441 D, V441 G, S464L, G465E, G465R, and S492R, and

b) administering to the patient the antibody composition.

43. An article of manufacture suitable for treating cancer in a patient, comprising an antibody composition comprising two anti-human EGFR antibodies that bind to distinct epitopes in the EGFR extracellular domain (ECD), wherein said treatment comprises:

a) selecting a patient with said cancer from whom a tumor DNA sample: i) has a mutant allele frequency (MAF) of less than 20% for (1 ) mutations in KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and

ii) has a MAF of less than 0.1 % for BRAF mutation V600E, and

b) administering to the patient the antibody composition.

44. The article of manufacture of claim 42 or 43, wherein the article is suitable for treating cancer in a patient in the method of any one of claims 1 -35.

45. A kit suitable for treating cancer in a patient from whom a tumor DNA sample: i) has a mutant allele frequency (MAF) of less than 20% for (1 ) mutations in KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146);

ii) has a MAF of less than 0.1 % for BRAF mutation V600E; and

iii) has a MAF of less than 0.1 % for EGFR ECD mutations V441 D, V441 G, S464L, G465E, G465R, and S492R,

wherein the kit comprises an antibody composition comprising two anti-human EGFR antibodies that bind to distinct epitopes in the EGFR extracellular domain (ECD).

46. A kit suitable for treating cancer in a patient from whom a tumor DNA sample: i) has a mutant allele frequency (MAF) of less than 20% for (1 ) mutations in KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61 ), and exon 4 (codons 1 17 and 146); and

ii) has a MAF of less than 0.1 % for BRAF mutation V600E;

wherein the kit comprises an antibody composition comprising two anti-human EGFR antibodies that bind to distinct epitopes in the EGFR extracellular domain (ECD).

47. The kit of claim 45 or 46, wherein the kit is suitable for treating cancer in a patient in the method of any one of claims 1 -35.

48. The use of claim 36 or 38, the antibody composition of claim 39 or 41 , the article of manufacture of claim 42 or 44, or the kit of claim 45 or 47, wherein the tumor DNA sample:

a) has no detectable levels of EGFR ECD mutations V441 D, V441 G, S464L, G465E, G465R, and S492R;

b) has no detectable levels of BRAF mutation V600E; or

c) both a) and b).

49. The use of any one of claims 36-38, the antibody composition of any one of claims 39-41 , the article of manufacture of any one of claims 42-44, or the kit of any one of claims 45-47, wherein the tumor DNA sample has no detectable levels of BRAF mutation V600E.

50. The use of any one of claims 36-38, the antibody composition of any one of claims 39-41 , the article of manufacture of any one of claims 42-44, or the kit of any one of claims 45-47, wherein the anti-EGFR antibody composition comprises a first anti-human EGFR antibody and a second anti-human EGFR antibody, wherein:

the first anti-human EGFR antibody comprises the heavy chain CDR1 , CDR2, and CDR3 in SEQ ID NO: 1 and the light chain CDR1 , CDR2, and CDR3 in SEQ ID NO: 2; and

the second anti-human EGFR antibody comprises the heavy chain CDR1 , CDR2, and CDR3 in SEQ ID NO: 3 and the light chain CDR1 , CDR2, and CDR3 in SEQ ID NO: 4.

51 . The use of any one of claims 36-38, the antibody composition of any one of claims 39-41 , the article of manufacture of any one of claims 42-44, or the kit of any one of claims 45-47, wherein the anti-EGFR antibody composition comprises a first anti-human EGFR antibody and a second anti-human EGFR antibody, wherein:

the first anti-human EGFR antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 and a light chain comprising the amino acid sequence of SEQ ID NO: 2; and

the second anti-human EGFR antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3 and a light chain comprising the amino acid sequence of SEQ ID NO: 4.

The use of any one of claims 36-38, the antibody composition of any one of claims 39-41 , the article of manufacture of any one of claims 42-44, or the kit of any one of claims 45-47, wherein the anti-EGFR antibody composition comprises a first anti-human EGFR antibody and a second anti-human EGFR antibody, wherein:

the first anti-human EGFR antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 26 and a light chain comprising the amino acid sequence of SEQ ID NO: 24; and

the second anti-human EGFR antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain comprising the amino acid sequence of SEQ ID NO: 25.