Anti-MDR1 antibodies and uses thereof
Provided are antibodies that target the cellular efflux pump MDR1. Also provided are pharmaceutical compositions, nucleic acids, recombinant expression vectors, cells, and kits that include or encode such antibodies. Methods of using the antibodies for detecting presence or absence of MDR1 expression in cells, e.g., tumor cells, level of MDR1 expression, and/or inhibiting MDR1 function are also disclosed. In addition, multi-specific antibodies that bind to MDR1 and a tumor associated antigen are provided. Also provided are methods for treating a subject for a cancer that include administering to the subject an anti-MDR1 antibody as disclosed herein or a multi-specific antibody that targets both MDR1 and a tumor associated antigen.
1 . An anti-multidrug resistance protein 1 (MDR1) antibody, wherein the antibody comprises: a variable heavy chain (VH) region comprising heavy chain complementarity determining region (HCDR) 1 comprising SEQ ID NO: 35; HCDR2 comprising SEQ ID NO: 36; and HCDR3 comprising SEQ ID NO: 37; and a variable light chain (VL) region comprising light chain complementarity determining region (LCDR) 1 comprising SEQ ID NO: 39; LCDR2 comprising SEQ ID NO: 40; and LCDR3 comprising SEQ ID NO: 329 or SEQ ID NO: 42.
2 . The anti-MDR1 antibody of claim 1 , wherein the VH region comprises SEQ ID NO: 34 and the VL region comprises SEQ ID NO: 313 or SEQ ID NO: 38.
3 . The anti-MDR1 antibody of claim 1 , wherein the antibody is humanized.
4 . The anti-MDR1 antibody of claim 1 , wherein the antibody is a bispecific antibody or a single chain Fv antibody.
5 . The anti-MDR1 antibody of claim 1 , wherein the antibody is conjugated to a toxic moiety.
6 . The anti-MDR1 antibody of claim 5 , wherein the toxic moiety is a chemotherapeutic agent.
7 . A pharmaceutical composition comprising the antibody of claim 1 , and a carrier or an excipient.
8 . A bispecific antibody that binds to MDR1 and CD47, the antibody comprising:
a common variable light chain (VL) region that binds to MDR1 and CD47 and comprises LCDRs 1-3 comprising SEQ ID NO:39, SEQ ID NO:40, and SEQ ID NO:329 or SEQ ID NO:42, respectively;
a first variable heavy chain (VH) region that binds to MDR1 and comprises HCDRs 1-3 comprising SEQ ID NO: 343; SEQ ID NO: 344; and SEQ ID NO: 345, respectively; and
a second VH region that binds to CD47 and comprises HCDRs 1-3 comprising SEQ ID NO: 346; SEQ ID NO: 347; and SEQ ID NO: 308, respectively.
9 . A method of treating a subject for a cancer expressing MDR1 and CD47, the method comprising administering to the subject a therapeutically effective amount of the antibody of claim 8 .
10 . The method of claim 9 , wherein the method comprises administering the antibody and at least one additional active agent to the subject, wherein the at least one additional active agent comprises a chemotherapy agent, an inhibitor of a multidrug resistance transporter, an immunotherapy agent, or a combination thereof.
11 . The method of claim 10 , wherein the at least one additional active agent is a chemotherapy agent.
12 . The method of claim 11 , wherein the chemotherapy agent is a taxol, a vinca alkaloid, or an anthracycline.
13 . The method of claim 10 , wherein the subject being treated has a cancer that is classified as being resistant to the chemotherapy agent.
14 . A method for inhibiting efflux activity of MDR1 expressed by a live cell, the method comprising contacting the cell with the antibody of claim 1 .
15 . The method of claim 14 , wherein the cell is a cancer cell.
16 . The method of claim 15 , wherein the cancer cell is a multidrug resistant cancer cell.