Anti-EGFR antibodies and their uses
View Patent ↗The present invention relates to antibodies directed to EGFR and uses of such antibodies, for example, to treat diseases associated with the activity and/or overproduction of EGFR.
1. A monoclonal antibody or a binding fragment thereof which:
(a) specifically binds to human EGFR;
(b) competes for binding to human EGFR with an antibody comprising a V H sequence of SEQ ID NO:1 and a V L sequence of SEQ ID NO:2;
(c) comprises six CDRs that altogether have up to seven amino acid substitutions, selected from one or more of Tables 3 to 14-3, as compared to the CDRs of SEQ ID NO:3 (CDR-H1), SEQ ID NO:4 (CDR-H2), SEQ ID NO:5 (CDR-H3), SEQ ID NO:6 (CDR-L1), SEQ ID NO:7 (CDR-L2), and SEQ ID NO:8 (CDR-L3), wherein any individual CDR has no more than three amino acid substitutions as compared to the corresponding CDR of SEQ ID NO:3 (CDR-H1), SEQ ID NO:4 (CDR-H2), SEQ ID NO:5 (CDR-H3), SEQ ID NO:6 (CDR-L1), SEQ ID NO:7 (CDR-L2), or SEQ ID NO:8 (CDR-L3); and
(d) has a substitution in CDR-L1 selected from G30Y, G30W, G30F, G30T, G30M, G30S, G30C, G30H, G30K, G30Q and G30R (as defined by Kabat numbering) as compared to a CDR-L1 of SEQ ID NO:6.
2. The monoclonal antibody or binding fragment of claim 1 , wherein the CDRs altogether have up to six amino acid substitutions as compared to the six CDRs of SEQ ID NO:3 (CDR-H1), SEQ ID NO:4 (CDR-H2), SEQ ID NO:5 (CDR-H3), SEQ ID NO:6 (CDR-L1), SEQ ID NO:7 (CDR-L2), and SEQ ID NO:8 (CDR-L3).
3. The monoclonal antibody or binding fragment of claim 1 , wherein the CDRs altogether have up to five amino acid substitutions as compared to the six CDRs of SEQ ID NO:3 (CDR-H1), SEQ ID NO:4 (CDR-H2), SEQ ID NO:5 (CDR-H3), SEQ ID NO:6 (CDR-L1), SEQ ID NO:7 (CDR-L2), and SEQ ID NO:8 (CDR-L3).
4. The monoclonal antibody or binding fragment of claim 1 , wherein the CDRs altogether have up to four amino acid substitutions as compared to the six CDRs of SEQ ID NO:3 (CDR-H1), SEQ ID NO:4 (CDR-H2), SEQ ID NO:5 (CDR-H3), SEQ ID NO:6 (CDR-L1), SEQ ID NO:7 (CDR-L2), and SEQ ID NO:8 (CDR-L3).
5. The monoclonal antibody or binding fragment of claim 4 , in which any individual CDR has no more than two amino acid substitutions as compared to the corresponding CDR of SEQ ID NO:3 (CDR-H1), SEQ ID NO:4 (CDR-H2), SEQ ID NO:5 (CDR-H3), SEQ ID NO:6 (CDR-L1), SEQ ID NO:7 (CDR-L2), and SEQ ID NO:8 (CDR-L3).
6. The monoclonal antibody or binding fragment of claim 1 , which comprises the CDR-H3 substitution Y98W (as defined by Kabat numbering) as compared to said CDR-H3 of SEQ ID NO:5.
7. The monoclonal antibody or binding fragment of claim 1 , which comprises the CDR-H2 substitution I51G (as defined by Kabat numbering) as compared to said CDR-H2 of SEQ ID NO:4.
8. The monoclonal antibody or binding fragment of claim 7 , which comprises the CDR-H3 substitution Y98W (as defined by Kabat numbering) as compared to said CDR-H3 of SEQ ID NO:5.
9. The monoclonal antibody or binding fragment of claim 1 , which comprises the CDR-L3 substitution N92L (as defined by Kabat numbering) as compared to said CDR-L3 of SEQ ID NO:8.
10. The monoclonal antibody or binding fragment of claim 8 , which comprises the CDR-L3 substitution N92L (as defined by Kabat numbering) as compared to said CDR-L3 of SEQ ID NO:8.
11. The monoclonal antibody or binding fragment of claim 1 , whose CDRs have amino acid sequences of SEQ ID NO:3 (CDR-H1), SEQ ID NO:4 (CDR-H2), SEQ ID NO:5 (CDR-H3), SEQ ID NO:233 (CDR-L1), SEQ ID NO:7 (CDR-L2), and SEQ ID NO:8 (CDR-L3).
12. The monoclonal antibody or binding fragment of claim 1 , whose CDRs have amino acid sequences of SEQ ID NO:3 (CDR-H1), SEQ ID NO:4 (CDR-H2), SEQ ID NO:230 (CDR-H3), SEQ ID NO:233 (CDR-L1), SEQ ID NO:7 (CDR-L2), and SEQ ID NO:8 (CDR-L3).
13. The monoclonal antibody or binding fragment of claim 1 , whose CDRs have amino acid sequences of SEQ ID NO:3 (CDR-H1), SEQ ID NO:207 (CDR-H2), SEQ ID NO:230 (CDR-H3), SEQ ID NO:233 (CDR-L1), SEQ ID NO:7 (CDR-L2), and SEQ ID NO:8 (CDR-L3).
14. The monoclonal antibody or binding fragment of claim 1 , which is a humanized antibody or anti-EGFR binding fragment of a humanized antibody, respectively.
15. The monoclonal antibody or binding fragment of claim 1 , which is an IgG.
16. The monoclonal antibody or binding fragment of claim 15 , which is an IgG 1 .
17. The monoclonal antibody or binding fragment of claim 1 , which is a bispecific antibody further comprising a binding portion specific for an antigen other than human EGFR.
18. The monoclonal antibody or binding fragment of claim 1 , which includes one or more mutations in the Fc region that increases ADCC activity.
19. The monoclonal antibody or binding fragment of claim 1 , which is non-fucosylated.
20. The monoclonal antibody or binding fragment of claim 1 , which includes one or more mutations in the Fc region that increases binding to FcγR.
21. The monoclonal antibody or binding fragment of claim 1 , which includes one or more mutations in the Fc region that increases binding to FcRn.
22. The monoclonal antibody or binding fragment of claim 1 , which includes one or more mutations in the Fc region that decreases ADCC activity.
23. The monoclonal antibody or binding fragment of claim 1 which has the heavy chain framework sequences of the V H sequence of SEQ ID NO:1 and the light chain framework sequences of the V L sequence of SEQ ID NO:2.
24. The monoclonal antibody or binding fragment of claim 1 which has the heavy chain framework sequences of the V H sequence of SEQ ID NO:9 and the light chain framework sequences of the V L sequence of SEQ ID NO:10.
25. The monoclonal antibody or binding fragment of claim 1 which is purified to at least 95% homogeneity.
26. An antibody-drug conjugate comprising a monoclonal antibody or binding fragment according to any one of claims 1 to 5 .
27. A pharmaceutical composition comprising a monoclonal antibody or binding fragment according to any one of claims 1 to 5 , and a pharmaceutically acceptable carrier.
28. A method of treating cancer expressing EGFR comprising administering to a human patient in need thereof a therapeutically effective amount of a monoclonal antibody or binding fragment according to claim 1 .
29. The method of claim 28 , wherein the cancer is squamous cell carcinoma of the head and neck.
30. The method of claim 28 , wherein the cancer is colorectal cancer.
31. The method of any one of claims 28 - 30 , further comprising administering to the patient at least one chemotherapeutic agent.
32. The method of claim 31 , wherein said at least one chemotherapeutic agent is a cytotoxic agent.
33. The method of claim 31 , wherein said at least one chemotherapeutic agent is selected from irinotecan, 5-fluorouracil, cisplatin, carboplatin, leucovorin calcium, capecitabine, and paclitaxel.
34. The method of claim 28 , further comprising administering radiation to said patient.
35. A method of treating cancer expressing EGFR comprising administering to a human patient in need thereof a therapeutically effective amount of an antibody-drug conjugate, wherein said antibody of the antibody-drug conjugate is a monoclonal antibody or binding fragment according to claim 1 .
36. The method of claim 35 , wherein the cancer is squamous cell carcinoma of the head and neck.
37. The method of claim 35 , wherein the cancer is colorectal cancer.
38. The method of any one of claims 35 - 37 , further comprising administering to the patient at least one chemotherapeutic agent.
39. The method of claim 38 , wherein said at least one chemotherapeutic agent is a cytotoxic agent.
40. The method of claim 38 , wherein said at least one chemotherapeutic agent is selected from irinotecan, 5-fluorouracil, cisplatin, carboplatin, leucovorin calcium, capecitabine, and paclitaxel.
41. The method of claim 35 , further comprising administering radiation to said patient.