BCMA monoclonal antibody-drug conjugate
The disclosure is directed to an antibody-drug conjugate (ADC) comprising a monoclonal antibody, or an antigen-binding fragment thereof, directed against B-cell maturation antigen (BCMA) conjugated to a cytotoxin. The disclosure also provides compositions comprising the antibody-drug conjugate and methods of killing multiple myeloma cells (including multiple myeloma stems cells) that express BCMA by contacting multiple myeloma cells with the ADC.
1. An antibody-drug conjugate (ADC) comprising a monoclonal antibody or an antigen-binding fragment thereof, conjugated to a cytotoxin, wherein the monoclonal antibody or antigen-binding fragment thereof is capable of binding to human B-cell maturation antigen (BCMA) and comprises (a) a heavy chain variable region comprising a complementarity determining region 1 (HCDR1) amino acid sequence of SEQ ID NO: 1, an HCDR2 amino acid sequence of SEQ ID NO: 2, and an HCDR3 amino acid sequence of SEQ ID NO: 3 and (b) a light chain variable region comprising a complementarity determining region 1 (LCDR1) amino acid sequence of SEQ ID NO: 4, an LCDR2 amino acid sequence of SEQ ID NO: 5, and an LCDR3 amino acid sequence of SEQ ID NO: 6.
2. The antibody-drug conjugate of claim 1 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7.
3. The antibody-drug conjugate of claim 1 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8.
4. The antibody-drug conjugate of claim 1 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8.
5. The antibody-drug conjugate of claim 1 , wherein the cytotoxin is an anti-microtubule agent, a pyrrolobenzodiazepine (PBD), an RNA polymerase II inhibitor, or a DNA alkylating agent.
6. The antibody-drug conjugate of claim 5 , wherein the cytotoxin is an anti-microtubule agent selected from the group consisting of a maytansinoid, an auristatin, and a tubulysin.
7. The antibody-drug conjugate of claim 5 , wherein the cytotoxin is a pyrrolobenzodiazepine (PBD).
8. The antibody-drug conjugate of claim 7 , wherein the pyrrolobenzodiapezine (PBD) is SG3249 having the following formula:
9. A composition comprising the antibody-drug conjugate of claim 1 and a pharmaceutically-acceptable carrier.
10. A monoclonal antibody or an antigen-binding fragment thereof, wherein the monoclonal antibody or antigen-binding fragment thereof is capable of binding to human B-cell maturation antigen (BCMA) and comprises (a) a heavy chain variable region comprising a complementarity determining region 1 (HCDR1) amino acid sequence of SEQ ID NO: 1, an HCDR2 amino acid sequence of SEQ ID NO: 2, and an HCDR3 amino acid sequence of SEQ ID NO: 3 and (b) a light chain variable region comprising a complementarity determining region 1 (LCDR1) amino acid sequence of SEQ ID NO: 4, an LCDR2 amino acid sequence of SEQ ID NO: 5, and an LCDR3 amino acid sequence of SEQ ID NO: 6.
11. The monoclonal antibody or antigen-binding fragment thereof of claim 10 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7.
12. The monoclonal antibody or antigen-binding fragment thereof of claim 10 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8.
13. The monoclonal antibody or antigen-binding fragment thereof of claim 10 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8.
14. A composition comprising the monoclonal antibody or antigen-binding fragment thereof of claim 10 and a pharmaceutically-acceptable carrier.