COMPOSITIONS AND METHODS FOR TREATING CANCER WITH ANTI-EGFR ANTIBODIES
The present invention provides methods and uses of anti-EGFR antibody compositions for treatment of cancers that are negative for certain mutations in RAS, BRAF, and the EGFR extracellular domain and are resistant to other anti-EGFR therapies.
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 117 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 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, V441G, 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 117 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 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 V441D, V441G, 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.
11 . 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 IgG1 or IgG2.
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 117 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 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 V441D, V441G, 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.
32 . 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 117 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 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 V441D, V441G, 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 117 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 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 V441D, V441G, 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 117 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 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 117 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 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, V441G, 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 117 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 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 117 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 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, V441G, 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 117 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 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 117 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 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 V441D, V441G, 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 117 and 146); and (2) mutations in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 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 V441D, V441G, 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.
52 . 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.