Bispecific anti-BCMA x anti-CD3 antibodies and uses thereof
B-cell maturation antigen (BCMA) is expressed on malignant plasma cells. The present invention provides novel bispecific antibodies (bsAbs) that bind to both BCMA and CD3 and activate T cells via the CD3 complex in the presence of BCMA-expressing tumor cells. In certain embodiments, the bispecific antigen-binding molecules of the present invention are capable of inhibiting the growth of tumors expressing BCMA. The bispecific antigen-binding molecules of the invention are useful for the treatment of diseases and disorders in which an upregulated or induced BCMA-targeted immune response is desired and/or therapeutically beneficial. For example, the bispecific antibodies of the invention are useful for the treatment of various cancers, including multiple myeloma.
1. An isolated bispecific antigen-binding molecule, comprising:
(a) a first antigen-binding domain that specifically binds human B cell maturation antigen (BCMA), and comprises HCDR1, HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 68, 70, 72, and LCDR1, LCDR2, LCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 84, 86, 88; and
(b) a second antigen-binding domain that specifically binds human CD3, and comprises HCDR1, HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 92, 94, 96, and LCDR1, LCDR2, LCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 84, 86, 88.
2. The isolated bispecific antigen-binding molecule of claim 1 , wherein:
(a) the first antigen-binding domain comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 66, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 82; and
(b) the0 second antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 90, and a LCVR comprising the amino acid sequence of SEQ ID NO: 82.
3. The isolated bispecific antigen-binding molecule of claim 1 that is a bispecific antibody.
4. The isolated bispecific antigen-binding molecule of claim 3 , wherein the bispecific antibody comprises a chimeric hinge that reduces Fcy receptor binding relative to a wild-type hinge of the same isotype.
5. The isolated bispecific antigen-binding molecule of claim 3 , wherein the bispecific antibody comprises a human IgG heavy chain constant region.
6. The isolated bispecific antigen-binding molecule of claim 5 , wherein the bispecific antibody comprises a human IgG1 heavy chain constant region.
7. The isolated bispecific antigen-binding molecule of claim 5 , wherein the bispecific antibody comprises a human IgG4 heavy chain constant region.
8. A pharmaceutical composition comprising the bispecific antigen-binding molecule of claim 1 , and a pharmaceutically acceptable carrier or diluent.
9. A pharmaceutical composition comprising the bispecific antigen-binding molecule of claim 2 , and a pharmaceutically acceptable carrier or diluent.
10. A pharmaceutical composition comprising the bispecific antibody of claim 6 , and a pharmaceutically acceptable carrier or diluent.
11. A pharmaceutical composition comprising the bispecific antibody of claim 7 , and a pharmaceutically acceptable carrier or diluent.
12. An isolated bispecific antigen-binding molecule, comprising:
(a) a first antigen-binding domain that specifically binds human B cell maturation antigen (BCMA), and comprises HCDR1, HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 68, 70, 72, and LCDR1, LCDR2, LCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 84, 86, 88; and
(b) a second antigen-binding domain that specifically binds human CD3, and comprises HCDR1, HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 100, 102, 104, and LCDR1, LCDR2, LCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 84, 86, 88.
13. The isolated bispecific antigen-binding molecule of claim 12 , wherein:
(a) the first antigen-binding domain comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 66, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 82; and
(b) the second antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 98, and a LCVR comprising the amino acid sequence of SEQ ID NO: 82.
14. The isolated bispecific antigen-binding molecule of claim 12 that is a bispecific antibody.
15. The isolated bispecific antigen-binding molecule of claim 14 , wherein the bispecific antibody comprises a chimeric hinge that reduces Fcy receptor binding relative to a wild-type hinge of the same isotype.
16. The isolated bispecific antigen-binding molecule of claim 14 , wherein the bispecific antibody comprises a human IgG heavy chain constant region.
17. The isolated bispecific antigen-binding molecule of claim 16 , wherein the bispecific antibody comprises a human IgG1 heavy chain constant region.
18. The isolated bispecific antigen-binding molecule of claim 16 , wherein the bispecific antibody comprises a human IgG4 heavy chain constant region.
19. A pharmaceutical composition comprising the bispecific antigen-binding molecule of claim 12 , and a pharmaceutically acceptable carrier or diluent.
20. A pharmaceutical composition comprising the bispecific antigen-binding molecule of claim 13 , and a pharmaceutically acceptable carrier or diluent.
21. A pharmaceutical composition comprising the bispecific antibody of claim 17 , and a pharmaceutically acceptable carrier or diluent.
22. A pharmaceutical composition comprising the bispecific antibody of claim 18 , and a pharmaceutically acceptable carrier or diluent.
23. A bispecific antibody, comprising:
(a) a first antigen-binding domain that specifically binds human B cell maturation antigen (BCMA), and comprises three heavy chain complementarity determining regions (CDRs) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 66, and three light chain CDRs contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 82; and
(b) a second antigen-binding domain that specifically binds human CD3, and comprises three heavy chain CDRs contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 90, and three light chain CDRs contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 82.
24. A bispecific antibody, comprising:
(a) a first antigen-binding domain that specifically binds human B cell maturation antigen (BCMA), and comprises three heavy chain complementarity determining regions (CDRs) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 66, and three light chain CDRs contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 82; and
(b) a second antigen-binding domain that specifically binds human CD3, and comprises three heavy chain CDRs contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 98, and three light chain CDRs contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 82.