Anti-PSMA antibodies, bispecific antigen-binding molecules that bind PSMA and CD3, and uses thereof
The present invention provides antibodies that bind to prostate-specific membrane antigen (PSMA), bispecific antibodies that bind to PSMA and CD3, and methods of using the same. According to certain embodiments, the antibodies of the invention bind human PSMA with high affinity and bind CD3 to induce human T cell proliferation. The invention includes antibodies that bind PSMA and CD3 and induce T cell-mediated killing of PSMA-expressing tumor cells. According to certain embodiments, the present invention provides bispecific antigen-binding molecules comprising a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding molecule that specifically binds human PSMA. In certain embodiments, the bispecific antigen-binding molecules of the present invention are capable of inhibiting the growth of prostate tumors expressing PSMA. The antibodies and bispecific antigen-binding molecules of the invention are useful for the treatment of diseases and disorders in which an upregulated or induced targeted immune response is desired and/or therapeutically beneficial. For example, the antibodies of the invention are useful for the treatment of various cancers.
1. A fully human bispecific antigen-binding molecule comprising a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding domain that specifically binds human PSMA, wherein:
(i) the first antigen-binding domain comprises one heavy chain polypeptide and one light chain polypeptide, and the second antigen-binding domain comprises one heavy chain polypeptide and one light chain polypeptide, wherein the second antigen-binding domain that specifically binds human PSMA comprises the heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) from a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 122, and the light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) from a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 930, and
(ii) the bispecific antigen-binding molecule induces T cell-mediated cell killing of PSMA-expressing cells.
2. The bispecific antigen-binding molecule of claim 1 , wherein the antigen-binding molecule inhibits tumor growth in immunocompetent mice bearing human prostate cancer xenografts.
3. The bispecific antigen-binding molecule of claim 1 , wherein the first antigen-binding domain that specifically binds human CD3 comprises heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) from a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 922, and light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) from a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 930.
4. The bispecific antigen-binding molecule of claim 1 , wherein the first antigen-binding domain that specifically binds human CD3 comprises three heavy chain complementarity determining regions (A1-HCDR1, A1-HCDR2 and A1-HCDR3) and three light chain complementarity determining regions (A1-LCDR1, A1-LCDR2 and A1-LCDR3), and wherein the second antigen-binding domain that specifically binds human PSMA comprises three heavy chain complementarity determining regions (A2-HCDR1, A2-HCDR2 and A2-HCDR3) and three light chain complementarity determining regions (A2-LCDR1, A2-LCDR2 and A2-LCDR3);
wherein A1-HCDR1 comprises the amino acid sequence of SEQ ID NO: 924; A1-HCDR2 comprises the amino acid sequence of SEQ ID NO: 926; A1-HCDR3 comprises the amino acid sequence of SEQ ID NO: 928; A1-LCDR1 comprises the amino acid sequence of SEQ ID NO: 932; A1-LCDR2 comprises the amino acid sequence of SEQ ID NO: 934; and A1-LCDR3 comprises the amino acid sequence of SEQ ID NO: 936; and
wherein A2-HCDR1 comprises the amino acid sequence of SEQ ID NO: 124; A2-HCDR2 comprises the amino acid sequence of SEQ ID NO: 126; A2-HCDR3 comprises the amino acid sequence of SEQ ID NO: 128; A2-LCDR1 comprises the amino acid sequence of SEQ ID NO: 932; A2-LCDR2 comprises the amino acid sequence of SEQ ID NO: 934; and A2-LCDR3 comprises the amino acid sequence of SEQ ID NO: 936.
5. A pharmaceutical composition comprising the bispecific antigen-binding molecule of claim 1 and a pharmaceutically acceptable carrier or diluent.
6. A bispecific antigen-binding molecule comprising a first antigen-binding domain that specifically binds human CD3 and comprises the complementarity determining regions (CDRs) of a heavy chain variable region/light chain variable region (HCVR/LCVR) pair comprising the amino acid sequences of SEQ ID NOs: 922/930; and a second antigen-binding domain that specifically binds human PSMA and comprises the CDRs of a HCVR/LCVR pair comprising the amino acid sequences of SEQ ID NOs: 122/930.
7. The bispecific antigen-binding molecule of claim 6 , wherein the first antigen-binding domain that specifically binds human CD3 comprises a heavy chain variable region/light chain variable region (HCVR/LCVR) pair comprising the amino acid sequences of SEQ ID NOs: 922/930, and the second antigen-binding domain that specifically binds human PSMA comprises a HCVR/LCVR pair comprising the amino acid sequences of SEQ ID NOs: 122/930.
8. A pharmaceutical composition comprising the bispecific antigen-binding molecule of claim 6 and a pharmaceutically acceptable carrier or diluent.
9. The bispecific antigen-binding molecule of claim 6 that is a bispecific antibody.
10. A pharmaceutical composition comprising the bispecific antigen-binding molecule of claim 4 and a pharmaceutically acceptable carrier or diluent.
11. A pharmaceutical composition comprising the bispecific antigen-binding molecule of claim 7 and a pharmaceutically acceptable carrier or diluent.
12. A pharmaceutical composition comprising the bispecific antibody of claim 9 and a pharmaceutically acceptable carrier or diluent.