Biparatopic FR-alpha antibodies and immunoconjugates
The present disclosure provides biparatopic antibodies comprising polypeptides that bind to folate receptor alpha (FRα) compositions comprising such biparatopic antibodies. In a specific aspect, the biparatopic antibodies bind to FRα and modulate FRα activity. The present disclosure also provides methods for treating disorders, such as cancer, by administering a biparatopic antibody that specifically binds to FRα and modulates FRα activity.
1. A method of treating a cancer in a subject, comprising administering to the subject a therapeutically effective amount of an immunoconjugate represented by the following formula:
or a pharmaceutically acceptable salt thereof, wherein:
CBA is a biparatopic antibody or an antigen-binding fragment comprising the amino acid sequences of SEQ ID NOs: 41-43;
D 1 is represented by the following formula:
and
q is an integer from 1 to 10, wherein said cancer is a human folate receptor 1 (FRα) expressing cancer.
2. The method of claim 1 , wherein the immunoconjugate is administered in a composition comprising an average Drug-Antibody Ratio (DAR) of 3-4.
3. A method of treating a cancer in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising an immunoconjugate represented by the following formula:
or a pharmaceutically acceptable salt thereof, wherein:
CBA is a bivalent biparatopic antibody or antigen-binding fragment thereof that specifically binds FRα, wherein the antibody or antigen-binding fragment comprises:
(i) a first FRα-binding domain comprising a first variable heavy chain (VH) and a first variable light chain (VL), wherein (a) the first VH comprises VH CDR1-3 comprising the amino acid sequences of SEQ ID NOs: 10-12, respectively, or SEQ ID NOs: 15, 16, and 12, respectively; and (b) the first VL comprises VL CDR1-3 comprising the amino acid sequences of SEQ ID NOs: 4-6, respectively; and
(ii) a second FRα-binding domain comprising a second VH and a second VL, wherein the second VH comprises VH CDR1-3 comprising the amino acid sequences of (a) SEQ ID NOs: 7-9, respectively, or (b) SEQ ID NOs: 13, 14, and 9, respectively; and the second VL comprises VL CDR1-3 comprising the amino acid sequences of SEQ ID NOs: 1-3, respectively;
wherein the first FRα-binding domain comprises an single-chain variable fragment (scFv) and the second FRα-binding domain comprises a VH and a VL on separate polypeptides or wherein the second FRα-binding domain comprises an single-chain variable fragment (scFv) and the first FRα-binding domain comprises a VH and a VL on separate polypeptides;
wherein the bivalent biparatopic antibody or antigen-binding fragment thereof comprises an IgG heavy chain constant region and a light chain constant region; and
wherein D 1 is represented by the following formula:
and
q is an integer from 1 to 10, wherein said cancer is a FRα expressing cancer.
4. The method of claim 3 , wherein the first VH of the bivalent biparatopic antibody or antigen-binding fragment comprises the amino acid sequence of SEQ ID NO:24, the first VL of the bivalent biparatopic antibody or antigen-binding fragment comprises the amino acid sequence of SEQ ID NO:19, the second VH of the bivalent biparatopic antibody or antigen-binding fragment comprises the amino acid sequence of SEQ ID NO:23, and the second VL of the bivalent biparatopic antibody or antigen-binding fragment comprises the amino acid sequence of SEQ ID NO:18.
5. The method of claim 3 , wherein the composition comprises a drug antibody ratio (DAR) of 3 to 4.
6. The method of claim 4 , wherein the composition comprises a drug antibody ratio (DAR) of 3 to 4.
7. The method of claim 3 wherein the cancer is ovarian cancer, uterine cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, or lung cancer.
8. The method of claim 3 , wherein the cancer is ovarian cancer.
9. The method of claim 8 , wherein the ovarian cancer is platinum-resistant epithelial ovarian cancer.
10. The method of claim 8 , wherein the ovarian cancer is relapsed epithelial ovarian cancer.
11. The method of claim 8 , wherein the ovarian cancer is platinum-refractory epithelial ovarian cancer.
12. The method of claim 2 , wherein the cancer is ovarian cancer, uterine cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, or lung cancer.
13. The method of claim 12 , wherein the cancer is ovarian cancer.
14. The method of claim 13 , wherein the ovarian cancer is platinum-resistant epithelial ovarian cancer.
15. The method of claim 13 , wherein the ovarian cancer is relapsed epithelial ovarian cancer.
16. The method of claim 13 , wherein the ovarian cancer is platinum-refractory epithelial ovarian cancer.
17. The method of claim 2 , wherein the cancer is uterine cancer.
18. The method of claim 2 , wherein the cancer is fallopian tube cancer.
19. The method of claim 2 , wherein the cancer is IMGN853-resistant.
20. The method of claim 6 , wherein the cancer is ovarian cancer, uterine cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, or lung cancer.
21. The method of claim 20 , wherein the cancer is ovarian cancer.
22. The method of claim 21 , wherein the ovarian cancer is platinum-resistant epithelial ovarian cancer.
23. The method of claim 21 , wherein the ovarian cancer is relapsed epithelial ovarian cancer.
24. The method of claim 21 , wherein the ovarian cancer is platinum-refractory epithelial ovarian cancer.
25. The method of claim 6 , wherein the cancer is uterine cancer.
26. The method of claim 6 , wherein the cancer is fallopian tube cancer.
27. The method of claim 6 , wherein the cancer is IMGN853-resistant.
28. The method of claim 8 , wherein the ovarian cancer is platinum sensitive ovarian cancer.
29. The method of claim 13 , wherein the ovarian cancer is platinum sensitive ovarian cancer.
30. The method of claim 21 , wherein the ovarian cancer is platinum sensitive ovarian cancer.