Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of thereof
The invention relates generally to antibodies that bind programmed death ligand 1 (PDL1), activatable antibodies that specifically bind to PDL1 and methods of making and using these anti-PDL1 antibodies and anti-PDL1 activatable antibodies in a variety of therapeutic, diagnostic and prophylactic indications.
1. An isolated antibody or antigen binding fragment thereof (AB) wherein the AB comprises:
(a) a heavy chain variable region (VH) comprising:
i. a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SEQ ID NO: 2.12;
ii. a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of SEQ ID NO: 246;
iii. a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of SEQ ID NO: 235; and
(b) a light chain variable region (VL) comprising:
i. a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of SEQ ID NO: 209;
ii. a variable light chain complementarity determining region 2 (VL CDR2) comprising an amino acid sequence of SEQ ID NOs: 215 or 227; and
iii. a variable light chain complementarity determining region 3 (VL CDR3) comprising the amino acid sequence of SEQ ID NO: 228,
wherein the AB specifically binds mammalian PDL1.
2. A conjugated antibody comprising the antibody of claim 1 conjugated to an agent.
3. The antibody of claim 1 , wherein the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 215.
4. A pharmaceutical composition comprising the antibody of claim 1 and a carrier.
5. A pharmaceutical composition comprising the conjugated antibody of claim 2 and a carrier.
6. An activatable antibody comprising the following structure:
(1) an antibody or an antigen binding fragment thereof (AB) that specifically binds to mammalian PDL1, wherein the AB comprises:
(a) a variable heavy chain region (VH) comprising:
i. a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SEQ ID NO: 212;
ii. a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of SEQ ID NO: 246; and
iii. a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of SEQ ID NO:235; and
(b) a variable light chain region (VL) comprising:
i. a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of SEQ ID NO: 209;
ii. a variable light chain complementarity determining region 2 (VL CDR2) comprising an amino acid sequence of SEQ ID NOs: 215 or 227; and
iii. a variable light chain complementarity determining region 3 (VL CDR3) comprising the amino acid sequence of SEQ ID NO: 228;
(2) a masking moiety (MM) comprising the amino acid sequence of SEQ ID NO: 63; and
(3) a cleavable moiety (CM) comprising the amino acid sequence of SEQ ID NO: 377.
7. The activatable antibody of claim 6 , wherein the AB is linked to the CM.
8. The activatable antibody of claim 7 , wherein the AB is linked directly to the CM.
9. The activatable antibody of claim 7 , wherein the AB is linked to the CM via a linking peptide.
10. The activatable antibody of claim 6 , wherein the MM is linked to the CM such that the activatable antibody in an uncleaved state comprises the structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM.
11. The activatable antibody of claim 10 , wherein the activatable antibody comprises a linking peptide between the MM and the CM, a linking peptide between the CM and the AB, or both a linking peptide between the MM and the CM and a linking peptide between the CM and the AB.
12. The activatable antibody of claim 10 , wherein the activatable antibody comprises a first linking peptide (LP1) and a second linking peptide (LP2), and wherein the activatable antibody in the uncleaved state has the structural arrangement from N-terminus to C-terminus as follows: MM-LP1-CM-LP2-AB or AB-LP2-CM-LP1-MM.
13. The activatable antibody of claim 12 , wherein the two linking peptides need not be identical to each other.
14. The activatable antibody of claim 12 , wherein each of LP1 and LP2 is a peptide of about 1 to 20 amino acids in length.
15. A conjugated activatable antibody comprising the activatable antibody of claim 6 conjugated to an agent.
16. The conjugated activatable antibody of claim 15 , wherein the agent has one or more of the following characteristics selected from the group consisting of:
(i) the agent is a toxin or fragment thereof;
(ii) the agent is a microtubule inhibitor;
(iii) the agent is a nucleic acid damaging agent;
(iv) the agent is a dolastatin or a derivative thereof;
(v) the agent is an auristatin or a derivative thereof;
(vi) the agent is a maytansinoid or a derivative thereof;
(vii) the agent is a duocarmycin or a derivative thereof;
(viii) the agent is a calicheamicin or a derivative thereof;
(ix) the agent is auristatin E or a derivative thereof;
(x) the agent is monomethyl auristatin E (MMAE);
(xi) the agent is monomethyl auristatin D (MMAD);
(xii) the agent is DM1;
(xiii) the agent is DM4;
(xiv) the agent is a detectable moiety;
(xv) the agent is a diagnostic agent;
(xvi) the agent is conjugated to the antibody via a linker;
(xvii) the agent is conjugated to the antibody via a cleavable linker; and
(xviii) the agent is conjugated to the antibody via a non-cleavable linker.
17. A pharmaceutical composition comprising the activatable antibody of claim 6 and a carrier.
18. The pharmaceutical composition of claim 17 comprising an additional agent.
19. The pharmaceutical composition of claim 18 , wherein the additional agent is a therapeutic agent.
20. The activatable antibody of claim 6 , wherein the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 215.
21. The activatable antibody of claim 6 , wherein the AB comprises a VH comprising the amino acid sequence of SEQ ID NO: 46 and a VL comprising the amino acid sequence of SEQ ID NO: 12.
22. The activatable antibody of claim 6 , wherein the AB comprises a VH comprising the amino acid sequence of SEQ ID NO: 46 and a VL comprising the amino acid sequence of SEQ ID NO: 58.
23. The activatable antibody of claim 6 , wherein the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 137 and a VH comprising the amino acid sequence of SEQ ID NO: 46.
24. The activatable antibody of claim 6 , wherein the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 985 and a VH comprising the amino acid sequence of SEQ ID NO: 46.
25. The activatable antibody of claim 6 , wherein the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 428 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 432.
26. The activatable antibody of claim 6 , wherein the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1008 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 432.
27. The pharmaceutical composition comprising the antibody of claim 3 and a carrier.
28. The pharmaceutical composition comprising the activatable antibody of claim 20 and a carrier.
29. A pharmaceutical composition comprising the activatable antibody of claim 25 and a carrier.
30. The pharmaceutical composition of claim 29 comprising an additional agent.
31. A pharmaceutical composition comprising the activatable antibody of claim 26 and a carrier.
32. A pharmaceutical composition comprising the activatable antibody of claim 24 and a carrier.
33. A pharmaceutical composition comprising the activatable antibody of claim 26 and a carrier.
34. A pharmaceutical composition comprising the conjugated activatable antibody of claim 15 and a carrier.
35. A method of reducing PDL1 activity comprising administering an effective amount of the antibody of claim 1 to a subject in need thereof.
36. A method of blocking binding of a natural ligand to PDL1 comprising administering an effective amount of the antibody of claim 1 to a subject in need thereof.
37. A method of treating, alleviating a symptom of, or delaying the progression of a PDL1-mediated disorder or disease comprising administering an effective amount of the antibody of claim 1 to a subject in need thereof.
38. A method of reducing PDL1 activity comprising administering an effective amount of the activatable antibody of claim 6 to a subject in need thereof.
39. A method of blocking binding of a natural ligand to PDL1 comprising administering an effective amount of the activatable antibody of claim 6 to a subject in need thereof.
40. A method of treating, alleviating a symptom of, or delaying the progression of a PDL1-mediated disorder or disease comprising administering a therapeutically effective amount of the activatable antibody of claim 6 to a subject in need thereof.
41. The method of claim 40 , wherein the PDL1-mediated disorder or disease is cancer.
42. The method of claim 41 , wherein the cancer is a bladder cancer, a bone cancer, a breast cancer, a carcinoid, a cervical cancer, a colon cancer, an endometrial cancer, a glioma, a head and neck cancer, a liver cancer, a lung cancer, a lymphoma, a melanoma, an ovarian cancer, a pancreatic cancer, a prostate cancer, a renal cancer, a sarcoma, a skin cancer, a stomach cancer, a testis cancer, a thyroid cancer, a urogenital cancer, or a urothelial cancer.
43. The method of claim 41 , wherein the cancer is selected from the group consisting of melanoma (MEL), renal cell carcinoma (RCC), squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, colorectal cancer (CRC), castration-resistant prostate cancer (CRPC), hepatocellular carcinoma (HCC), squamous cell carcinoma of the head and neck, carcinomas of the esophagus, ovary, gastrointestinal tract and breast, or a hematologic malignancy such as multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma/primary mediastinal B-cell lymphoma, and chronic myelogenous leukemia.
44. The method of claim 40 , wherein the method comprises administering an additional agent.
45. The method of claim 44 , wherein the additional agent is a therapeutic agent.
46. The method of claim 40 , wherein the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 428 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 432, and wherein the PDL1-mediated disorder or disease is cancer.
47. The method of claim 40 , wherein the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1008 and aheavy chain comprising the amino acid sequence of SEQ ID NO: 432, and wherein the PDL1-mediated disorder or disease is cancer.
48. The method of claim 40 , wherein the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 985 and a VH comprising the amino acid sequence of SEQ ID NO: 46, and wherein the PDL1-mediated disorder or disease is cancer.