Anti-mertk agonistic antibodies and uses thereof
The present disclosure provides antibody-drug conjugates comprising (i) antibodies that specifically bind to Mer Tyrosin Kinase (MERTK) (e.g., human MERTK, or both human and mouse MERTK), and (ii) cytotoxic agents conjugated directly to the antibodies or conjugated to the antibodies via linkers, and compositions comprising such antibody-drug conjugates, wherein the antibodies contained in the antibody-drug conjugates agonize MERTK signaling of endothelial cells. The present disclosure also provides methods for treating cancer, by administering an antibody-drug conjugate that comprises (i) an antibody that specifically binds to MERTK and agonizes MERTK signaling of endothelial cells, and (ii) a cytotoxic agent conjugated directly to the antibody or conjugated to the antibody via a linker.
1. An antibody-drug conjugate comprising:
(a) an antibody moiety that is an antibody or antigen-binding fragment thereof that specifically binds to human MERTK; (b) one or more drug moieties, each drug moiety being a cytotoxic agent; and (c) optionally a linker; wherein the cytotoxic agent is conjugated directly to the antibody moiety or is conjugated to the antibody moiety via the linker; wherein said antibody or antigen-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein
(i) the VH comprises a CDR 1 of SEQ ID NO: 1, a CDR2 of SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 11; and the VL comprises a CDR1 of SEQ ID NO: 15, a CDR2 of SEQ ID NO: 19, and a CDR3 of SEQ ID NO: 22; or
(ii) the VH comprises a CDR1 of SEQ ID NO: 2, a CDR2 of SEQ ID NO: 7, and a CDR3 of SEQ ID NO: 12; and the VL comprises a CDR1 of SEQ ID NO: 16, a CDR2 of SEQ ID NO: 20, and a CDR3 of SEQ ID NO: 23; or
(iii) the VH comprises a CDR1 of SEQ ID NO: 3, a CDR2 of SEQ ID NO: 8, and a CDR3 of SEQ ID NO: 11; and the VL comprises a CDR1 of SEQ ID NO: 15, a CDR2 of SEQ ID NO: 19 and a CDR3 of SEQ ID NO: 22; or
(iv) the VH comprises a CDR1 of SEQ ID NO: 4, a CDR2 of SEQ ID NO: 9, and a CDR3 of SEQ ID NO: 13; and the VL comprises a CDR1 of SEQ ID NO: 17, a CDR2 of SEQ ID NO: 21, and a CDR3 of SEQ ID NO: 24; or
(v) the VH comprises a CDR1 of SEQ ID NO: 5, a CDR2 of SEQ ID NO: 10, and a CDR3 of SEQ ID NO: 14; and the VL comprises CDR1 of SEQ ID NO: 18, a CDR2 of SEQ ID NO: 20, and a CDR3 of SEQ ID NO: 22; or
(vi) the VH comprises a CDR1 of SEQ ID NO: 3, a CDR2 of SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 11; and the VL comprises a CDR1 of SEQ ID NO: 15, a CDR2 of SEQ ID NO: 19 and a CDR3 of SEQ ID NO: 22; or
(vii) the VH comprises a CDR1 of SEQ ID NO: 25, a CDR2 of SEQ ID NO: 30, and a CDR3 of SEQ ID NO: 35; and the VL comprises a CDR1 of SEQ ID NO: 39, a CDR2 of SEQ ID NO: 43, and a CDR3 of SEQ ID NO:46;
(viii) the VH comprises a CDR1 of SEQ ID NO: 26, a CDR2 of SEQ ID NO: 31, and a CDR3 of SEQ ID NO: 36; and the VL comprises a CDR1 of SEQ ID NO: 40, a CDR2 of SEQ ID NO: 44, and a CDR3 of SEQ ID NO: 47; or
(ix) the VH comprises a CDR1 of SEQ ID NO: 27, a CDR2 of SEQ ID NO: 32, and a CDR3 of SEQ ID NO: 35; and the VL comprises a CDR1 of SEQ ID NO: 39, a CDR2 of SEQ ID NO: 43, and a CDR3 of SEQ ID NO: 46; or
(x) the VH comprises a CDR1 of SEQ ID NO: 28, a CDR2 of SEQ ID NO: 33, and a CDR3 of SEQ ID NO: 37; and the VL comprises a CDR1 of SEQ ID NO: 41, a CDR2 of SEQ ID NO: 45, and a CDR3 of SEQ ID NO: 48; or
(xi) the VH comprises a CDR1 of SEQ ID NO: 29, a CDR2 of SEQ ID NO: 34, and a CDR3 of SEQ ID NO: 38; and the VL comprises a CDR1 of SEQ ID NO: 42, a CDR2 of SEQ ID NO: 44, and a CDR3 of SEQ ID NO: 46; or
(xii) the VH comprises a CDR1 of SEQ ID NO: 27, a CDR2 of SEQ ID NO: 30, and a CDR3 of SEQ ID NO: 35; and the VL comprises a CDR1 of SEQ ID NO: 39, a CDR2 of SEQ ID NO: 43, and a CDR3 of SEQ ID NO: 46.
2. The antibody-drug conjugate of claim 1 , wherein
(i) the VH comprises a CDR 1 of SEQ ID NO: 1, a CDR2 of SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 11; and the VL comprises a CDR1 of SEQ ID NO: 15, a CDR2 of SEQ ID NO: 19, and a CDR3 of SEQ ID NO: 22; or
(ii) the VH comprises a CDR1 of SEQ ID NO: 2, a CDR2 of SEQ ID NO: 7, and a CDR3 of SEQ ID NO: 12; and the VL comprises a CDR1 of SEQ ID NO: 16, a CDR2 of SEQ ID NO: 20, and a CDR3 of SEQ ID NO: 23; or
(iii) the VH comprises a CDR1 of SEQ ID NO: 3, a CDR2 of SEQ ID NO: 8, and a CDR3 of SEQ ID NO: 11; and the VL comprises a CDR1 of SEQ ID NO: 15, a CDR2 of SEQ ID NO: 19 and a CDR3 of SEQ ID NO: 22; or
(iv) the VH comprises a CDR1 of SEQ ID NO: 4, a CDR2 of SEQ ID NO: 9, and a CDR3 of SEQ ID NO: 13; and the VL comprises a CDR1 of SEQ ID NO: 17, a CDR2 of SEQ ID NO: 21, and a CDR3 of SEQ ID NO: 24; or
(v) the VH comprises a CDR1 of SEQ ID NO: 5, a CDR2 of SEQ ID NO: 10, and a CDR3 of SEQ ID NO: 14; and the VL comprises CDR1 of SEQ ID NO: 18, a CDR2 of SEQ ID NO: 20, and a CDR3 of SEQ ID NO: 22; or
(vi) the VH comprises a CDR1 of SEQ ID NO: 3, a CDR2 of SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 11; and the VL comprises a CDR1 of SEQ ID NO: 15, a CDR2 of SEQ ID NO: 19 and a CDR3 of SEQ ID NO: 22.
3. The antibody-drug conjugate of claim 2 , wherein the antibody is an immunoglobulin.
4. The antibody-drug conjugate of claim 1 , wherein the antibody or antigen-binding fragment is humanized.
5. The antibody-drug conjugate of claim 2 , wherein the antibody or antigen-binding fragment comprises a human-derived constant region.
6. The antibody-drug conjugate of claim 3 , wherein the antibody is a humanized immunoglobulin.
7. The antibody-drug conjugate of claim 1 , wherein the antibody is a bispecific antibody.
8. An antibody-drug conjugate comprising: (I) an antibody moiety that is an immunoglobulin that specifically binds to human MERTK, said immunoglobulin comprising:
(A) (i) a heavy chain variable region that comprises the amino acid sequence of SEQ ID NO: 51, and (ii) a light chain variable region that comprises the amino acid sequence of SEQ ID NO: 52; or
(B) (i) a heavy chain variable region that comprises the amino acid sequence of SEQ ID NO: 49, and (ii) a light chain variable region that comprises the amino acid sequence of SEQ ID NO: 50;
(II) one or more drug moieties, each drug moiety being a cytotoxic agent; and
(III) optionally a linker;
wherein the cytotoxic agent is conjugated directly to the antibody moiety or is conjugated to the antibody moiety via the linker.
9. An antibody-drug conjugate comprising:
(I) an antibody moiety that is an antibody that competes for binding to MERTK with a reference antibody selected from the group consisting of:
(a) a first immunoglobulin comprising (i) a heavy chain variable region that comprises the amino acid sequence of SEQ ID NO: 51, and (ii) a light chain variable region that comprises the amino acid sequence of SEQ ID NO: 52; and
(b) a second immunoglobulin comprising (i) a heavy chain variable region that comprises the amino acid sequence of SEQ ID NO: 49, and (ii) a light chain variable region that comprises the amino acid sequence of SEQ ID NO: 50;
(II) one or more drug moieties, each drug moiety being a cytotoxic agent; and
(III) optionally a linker;
wherein the cytotoxic agent is conjugated directly to the antibody moiety or is conjugated to the antibody moiety via the linker.
10. The antibody-drug conjugate of claim 1 , which has a molar ratio of the antibody moiety to the drug moiety that is between 1:1 and 1:12.
11. The antibody-drug conjugate of claim 1 , wherein the antibody-drug conjugate comprises the linker, and the linker is a cleavable linker.
12. The antibody-drug conjugate of claim 1 , wherein the antibody-drug conjugate comprises the linker, and the linker is a non-cleavable linker.
13. The antibody-drug conjugate of claim 1 , wherein the cytotoxic agent is an auristatin, a maytansinoid, a pyrrolobenzodiazepine, an indolinobenzodiazepine, a calicheamicin, a camptothecin analogue, a duocarmycin, a tubulin inhibitor, a tubulysin or tubulysin analogue, amberstatin269, doxorubicin, an antibiotic, an anthracycline, a microtubule inhibitor, a spliceostatin, or a thailanstatin.
14. The antibody-drug conjugate of claim 13 , wherein the cytotoxic agent is monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF).
15. The antibody-drug conjugate of claim 13 , wherein the cytotoxic agent is SN38.
16. A method of producing the antibody-drug conjugate of any of claim 1 , wherein said antibody-drug conjugate comprises said linker, said method comprising the following steps in the order stated: (a) conjugating the linker directly to the cytotoxic agent to produce a linker-cytotoxic agent moiety; (b) conjugating the linker of the linker-cytotoxic agent moiety directly to the antibody moiety to produce the antibody-drug conjugate; and (c) purifying the antibody-drug conjugate.
17. A pharmaceutical composition comprising a therapeutically effective amount of the antibody-drug conjugate of claim 1 ; and a pharmaceutically acceptable carrier.
18. A method of treating cancer in a subject in need thereof, comprising administering to said subject the pharmaceutical composition of claim 17 .
19. The method of claim 18 , wherein said cancer is a cancer of the lung, breast, bone, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate or thyroid, or said cancer is a sarcoma, squamous cell carcinoma, melanoma, glioma, glioblastoma, neuroblastoma or Kaposi's sarcoma.
20. The method of claim 19 , wherein said cancer is breast cancer.
21. The method of claim 20 , wherein said cancer is triple-negative breast cancer.
22. The method of claim 18 , wherein said subject is a human.
23. The antibody-drug conjugate of claim 1 , wherein
(i) the VH comprises a CDR1 of SEQ ID NO: 25, a CDR2 of SEQ ID NO: 30, and a CDR3 of SEQ ID NO: 35; and the VL comprises a CDR1 of SEQ ID NO: 39, a CDR2 of SEQ ID NO: 43, and a CDR3 of SEQ ID NO:46;
(ii) the VH comprises a CDR1 of SEQ ID NO: 26, a CDR2 of SEQ ID NO: 31, and a CDR3 of SEQ ID NO: 36; and the VL comprises a CDR1 of SEQ ID NO: 40, a CDR2 of SEQ ID NO: 44, and a CDR3 of SEQ ID NO: 47; or
(iii) the VH comprises a CDR1 of SEQ ID NO: 27, a CDR2 of SEQ ID NO: 32, and a CDR3 of SEQ ID NO: 35; and the VL comprises a CDR1 of SEQ ID NO: 39, a CDR2 of SEQ ID NO: 43, and a CDR3 of SEQ ID NO: 46; or
(iv) the VH comprises a CDR1 of SEQ ID NO: 28, a CDR2 of SEQ ID NO: 33, and a CDR3 of SEQ ID NO: 37; and the VL comprises a CDR1 of SEQ ID NO: 41, a CDR2 of SEQ ID NO: 45, and a CDR3 of SEQ ID NO: 48; or
(v) the VH comprises a CDR1 of SEQ ID NO: 29, a CDR2 of SEQ ID NO: 34, and a CDR3 of SEQ ID NO: 38; and the VL comprises a CDR1 of SEQ ID NO: 42, a CDR2 of SEQ ID NO: 44, and a CDR3 of SEQ ID NO: 46; or
(vi) the VH comprises a CDR1 of SEQ ID NO: 27, a CDR2 of SEQ ID NO: 30, and a CDR3 of SEQ ID NO: 35; and the VL comprises a CDR1 of SEQ ID NO: 39, a CDR2 of SEQ ID NO: 43, and a CDR3 of SEQ ID NO: 46.
24. The antibody-drug conjugate of claim 23 , wherein the antibody is an immunoglobulin.
25. The antibody-drug conjugate of claim 24 , wherein the antibody is a humanized immunoglobulin.
26. The antibody-drug conjugate of claim 23 , wherein the antibody or antigen-binding fragment comprises a human-derived constant region.
27. The antibody-drug conjugate of claim 8 , wherein the immunoglobulin comprises
(i) a heavy chain variable region that comprises the amino acid sequence of SEQ ID NO: 49, and
(ii) a light chain variable region that comprises the amino acid sequence of SEQ ID NO: 50.
28. A pharmaceutical composition comprising a therapeutically effective amount of the antibody-drug conjugate of claim 2 ; and a pharmaceutically acceptable carrier.
29. A pharmaceutical composition comprising a therapeutically effective amount of the antibody-drug conjugate of claim 3 ; and a pharmaceutically acceptable carrier.
30. A pharmaceutical composition comprising a therapeutically effective amount of the antibody-drug conjugate of claim 5 ; and a pharmaceutically acceptable carrier.
31. A pharmaceutical composition comprising a therapeutically effective amount of the antibody-drug conjugate of claim 8 ; and a pharmaceutically acceptable carrier.
32. A pharmaceutical composition comprising a therapeutically effective amount of the antibody-drug conjugate of claim 23 ; and a pharmaceutically acceptable carrier.
33. A pharmaceutical composition comprising a therapeutically effective amount of the antibody-drug conjugate of claim 25 ; and a pharmaceutically acceptable carrier.
34. A method of treating cancer in a subject in need thereof, comprising administering to said subject the pharmaceutical composition of claim 28 .
35. A method of treating cancer in a subject in need thereof, comprising administering to said subject the pharmaceutical composition of claim 29 .
36. A method of treating cancer in a subject in need thereof, comprising administering to said subject the pharmaceutical composition of claim 30 .
37. A method of treating cancer in a subject in need thereof, comprising administering to said subject the pharmaceutical composition of claim 31 .
38. A method of treating cancer in a subject in need thereof, comprising administering to said subject the pharmaceutical composition of claim 32 .
39. A method of treating cancer in a subject in need thereof, comprising administering to said subject the pharmaceutical composition of claim 33 .