Bispecific pd-l1xcd28 antibodies and methods of use thereof

Abstract

The present disclosure provides bispecific antigen-binding molecules that bind to PD-L1 and CD28 (PD-L1xCD28). In certain embodiments, the present disclosure provides fora bispecific PD-L1xCD28 antigen-binding molecule (or antibody) or antigen-binding fragment thereof comprising a first antigen-binding domain that specifically binds CD28, and a second antigen binding domain that specifically binds PD-L1. In certain embodiments, the bispecific antigen binding molecules of the present disclosure bind CD28 on T-cells with the first antigen-binding domain and PD-L1 expressed on tumor cells or antigen presenting cells with the second antigenbinding domain. In certain embodiments, the bispecific antigen-binding molecules are capable of inhibiting growth of a tumor. The bispecific antigen-binding molecules of this disclosure are useful for treatment of cancer.

Description

This disclosure provides a bispecific antigen-binding molecule (PD-L1xCD28) that binds to PD-L1 and CD28. In some embodiments, this disclosure provides a bispecific PD-L1xCD28 antigen-binding molecule (or antibody) or its antigen-binding fragment comprising a first antigen-binding domain that specifically binds to CD28 and a second antigen-binding domain that specifically binds to PD-L1. In some embodiments, the bispecific antigen-binding molecule of this disclosure binds to CD28 on T cells with the first antigen-binding domain and binds to PD-L1 expressed on tumor cells or antigen-presenting cells with the second antigen-binding domain. In some embodiments, the bispecific antigen-binding molecule is capable of inhibiting tumor growth. The bispecific antigen-binding molecule of this disclosure can be used to treat cancer. Abstract

Claims

We claim:

1. An isolated bispecific antigen-binding molecule comprising:(a) a first antigen-binding domain that specifically binds human CD28, with a KDof less than about 3x108M as measured by surface plasmon resonance at 25°C; and(b) a second antigen-binding domain that specifically binds a human programmed death- ligand 1 (PD-L1) with a KDof less than about 2x10’wM as measured by surface plasmon resonance at 25°C.

2. The isolated bispecific antigen-binding molecule of claim 1 , wherein the bispecific antigen-binding molecule binds to the surface of human T cells with an ECso of less than about 2x1 O'8M as measured by an in vitro FACS binding assay.

3. The isolated bispecific antigen-binding molecule of claim 1 or 2, wherein the bispecific antigen-binding molecule binds to the surface of a cell expressing PD-L1 with an ECso of less than about 3x1 O'9M as measured by an in vitro FACS binding assay.

4. The isolated bispecific antigen-binding molecule of any one of claims 1-3, wherein the bispecific antigen-binding molecule blocks PD-L1 binding to PD-1 with an ICso of less than about 1.3nM as measured by an ELISA-based blocking assay.

5. The isolated bispecific antigen-binding molecule of any one of claims 1-4, wherein the bispecific antigen-binding molecule, in combination with a bispecific MUC16xCD3 antibody mediates in vitro T cell killing of OVCAR-3 cells expressing PD-L1 with an ECso of less than about 10’10M.

6. The isolated bispecific antigen-binding molecule of any one of claims 1-5, wherein the first antigen-binding domain comprises:(a) three heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 50, 32 and 10, or a variant thereof; and(b) three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 58 and 18, or a variant thereof.

7. The isolated bispecific antigen-binding molecule of claim 6, comprising a HCDR1 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 52, 34 and 12, a HCDR2 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 54, 36 and 14, and a HCDR3 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 56, 38 and 16.

8. The isolated bispecific antigen-binding molecule of claim 6 or 7, comprising a LCDR1 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 60 and 20, a LCDR2 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 62 and 22, and a LCDR3 comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 64 and 24.

9. The isolated bispecific antigen-binding molecule of claim 7 or 8, wherein the first antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 50, or a variant thereof, and a LCVR comprising the amino acid sequence of SEQ ID NO: 58, or a variant thereof.

10. The isolated bispecific antigen-binding molecule of claim 7 or 8, wherein the first antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 32, or a variant thereof, and a LCVR comprising the amino acid sequence of SEQ ID NO: 18, or a variant thereof.

11. The isolated bispecific antigen-binding molecule of claim 7 or 8, wherein the first antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof, and a LCVR comprising the amino acid sequence of SEQ ID NO: 18, or a variant thereof.

12. The isolated bispecific antigen-binding molecule of any one of claims 1-11 , wherein the second antigen-binding domain comprises:(a) three heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 42 and 2, or a variant thereof; and(b) three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 58 and 18, or a variant thereof.

13. The isolated bispecific antigen-binding molecule of claim 12, wherein the second antigen-binding domain comprises:(a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 4;(b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46 or SEQ ID NO: 6; and(c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48 or SEQ ID NO: 8.

14. The isolated bispecific antigen-binding molecule of claim 12 or 13, wherein the second antigen-binding domain comprises a LCDR1 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 60 and 20, a LCDR2 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 62 and 22, and a LCDR3 comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 64 and 24.

15. The isolated bispecific antigen-binding molecule of claim 14, wherein the second antigen-binding domain comprises:(a) HCDR1 , HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 44, 46, 48; and LCDR1 , LCDR2, LCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 60, 62, 64; or(b) HCDR1 , HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 4, 6, 8; and LCDR1, LCDR2, LCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 20, 22, 24.

16. The isolated bispecific antigen-binding molecule of claim 15, wherein the second antigen-binding domain comprises:(a) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, or a variant thereof, and a LCVR comprising the amino acid sequence of SEQ ID NO: 58, or a variant thereof; or(b) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, or a variant thereof, and a LCVR comprising the amino acid sequence of SEQ ID NO: 18, or a variant thereof.

17. An isolated bispecific antigen-binding molecule, comprising:(a) a first antigen-binding domain that specifically binds human CD28 wherein the first antigen-binding domain comprises HCDR1 , HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 52,54, 56, and LCDR1 , LCDR2, LCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 60,62,64; and(b) a second antigen-binding domain that specifically binds human PD-L1 wherein the second antigen-binding domain comprises HCDR1 , HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 44,46,48, and LCDR1 , LCDR2, LCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 60, 62, 64.

18. An isolated bispecific antigen-binding molecule, comprising:(a) a first antigen-binding domain that specifically binds human CD28 wherein the first antigen-binding domain comprises HCDR1 , HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 34, 36, 38, and LCDR1 , LCDR2, LCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 20, 22, 24; and(b) a second antigen-binding domain that specifically binds human PD-L1 wherein the second antigen-binding domain comprises HCDR1 , HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 4, 6, 8, and LCDR1 , LCDR2, LCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 20, 22, 24.

19. An isolated bispecific antigen-binding molecule, comprising:(a) a first antigen-binding domain that specifically binds human CD28 wherein the first antigen-binding domain comprises HCDR1 , HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 12,14,16, and LCDR1 , LCDR2, LCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 20, 22, 24; and(b) a second antigen-binding domain that specifically binds human PD-L1 wherein the second antigen-binding domain comprises HCDR1 , HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 4,6,8, and LCDR1 , LCDR2, LCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 20, 22, 24.

20. The isolated bispecific antigen-binding molecule of claim 17, comprising:(a) a first antigen-binding domain that comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 50, and a LCVR comprising the amino acid sequence of SEQ ID NO: 58; and(b) a second antigen-binding domain that comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and a LCVR comprising the amino acid sequence of SEQ ID NO: 58.

21. The isolated bispecific antigen-binding molecule of claim 18, comprising:(a) a first antigen-binding domain that comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and a LCVR comprising the amino acid sequence of SEQ ID NO: 18; and(b) a second antigen-binding domain that comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and a LCVR comprising the amino acid sequence of SEQ ID NO: 18.

22. The isolated bispecific antigen-binding molecule of claim 19, comprising:(a) a first antigen-binding domain that comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 10, and a LCVR comprising the amino acid sequence of SEQ ID NO: 18; and(b) a second antigen-binding domain that comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and a LCVR comprising the amino acid sequence of SEQ ID NO: 18.

23. An isolated bispecific antigen-binding molecule that competes for binding to PD-L1 or binds to the same epitope on PD-L1 as a reference antibody, wherein the reference antibody comprises a first antigen-binding domain comprising an HCVR / LCVR pair comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 50 / 58, 32 / 18 and 10 / 18 and a second antigen-binding domain comprising an HCVR / LCVR pair comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 42 / 58 and 2 / 18.

24. An isolated bispecific antigen-binding molecule that competes for binding to human CD28 or binds to the same epitope on human CD28 as a reference antibody, wherein the reference antibody comprises a first antigen-binding domain comprising an HCVR / LCVR paircomprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 50 / 58, 32 / 18 and 10 / 18 and a second antigen-binding domain comprising an HCVR / LCVR pair comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 42 / 58 and 2 / 18.

25. The isolated bispecific antigen-binding molecule of any one of claim 1-24 that is a human bispecific antigen-binding molecule.

26. The isolated bispecific antigen-binding molecule of any one of claim 1-25 that is a bispecific antibody.

27. The isolated bispecific antigen-binding molecule of 26, wherein the antibody comprises a human IgG heavy chain constant region attached, respectively, to the HCVR of each of the first antigen-binding domain and the second antigen-binding domain.

28. The isolated bispecific antigen-binding molecule of claim 27, wherein the heavy chain constant region is of isotype lgG1.

29. The isolated bispecific antigen-binding molecule of claim 27, wherein the heavy chain constant region is of isotype lgG4.

30. The isolated bispecific antigen-binding molecule of any one of claims 27 to 29, wherein the heavy chain constant region attached to the HCVR of the first antigen-binding domain, or the heavy chain constant region attached to the HCVR of the second antigen-binding domain, but not both, contains an amino acid modification that reduces Protein A binding relative to a heavy chain of the same isotype without the modification.

31. The isolated bispecific antigen-binding molecule of claim 30, wherein the modification comprises a H435R substitution (EU numbering) in a heavy chain of isotype IgG 1 or lgG4.

32. The isolated bispecific antigen-binding molecule of claim 30, wherein the modification comprises a H435R substitution and a Y436F substitution (EU numbering) in a heavy chain of isotype lgG1 or lgG4.

33. The isolated bispecific antigen-binding molecule of any one of claims 28-32, wherein the bispecific antibody comprises a chimeric hinge that reduces Fey receptor binding relative to a wild-type hinge of the same isotype.

34. The isolated bispecific antigen-binding molecule of any one of claims 27 to 33, wherein the antibody comprises a first heavy chain containing the HCVR of the first antigen-binding domain and a second heavy chain containing the HCVR of the second antigen-binding domain, wherein the first heavy chain comprises the amino acid sequence selected from the group consisting of SEQ ID NOs: 68, 40 and 28; and the second heavy chain comprises the amino acid sequence selected from the group consisting of SEQ ID NOs: 66 and 26.

35. The isolated bispecific antigen-binding molecule of claim 34, wherein the antibody comprises a common light chain containing the LCVR of the first and second antigen-binding domains, wherein the common light chain comprises the amino acid sequence selected from the group consisting of SEQ ID NOs: 70 and 30.

36. The isolated bispecific antigen-binding molecule of any one of claims 27 to 33, wherein the antibody comprises a first heavy chain containing the HCVR of the first antigen-binding domain and a second heavy chain containing the HCVR of the second antigen-binding domain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 68 and the second heavy chain comprises the amino acid sequence of SEQ ID NO: 66.

37. The isolated bispecific antigen-binding molecule of claim 36, wherein the antibody comprises a common light chain containing the LCVR of the first and second antigen-binding domains, wherein the common light chain comprises the amino acid sequence of SEQ ID NOs: 70.

38. A bispecific antibody comprising a first antigen-binding domain that binds specifically to human CD28 and a second antigen-binding domain that binds specifically to human PD-L1 , wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 68 paired with a common light chain comprising the amino acid sequence of SEQ ID NO: 70, and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 66 paired with a common light chain comprising the amino acid sequence of SEQ ID NO: 70.

39. A bispecific antibody comprising a first antigen-binding domain that binds specifically to human CD28 and a second antigen-binding domain that binds specifically to human PD-L1 , wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 40 paired with a common light chain comprising the amino acid sequence of SEQ ID NO: 30, and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 26 paired with a common light chain comprising the amino acid sequence of SEQ ID NO: 30.

40. A bispecific antibody comprising a first antigen-binding domain that binds specifically to human CD28 and a second antigen-binding domain that binds specifically to human PD-L1 , wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 28 paired with a common light chain comprising the amino acid sequence of SEQ ID NO: 30, and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 26 paired with a common light chain comprising the amino acid sequence of SEQ ID NO: 30.

41. The bispecific antibody of any one of claims 38-40 that is a human antibody.

42. A pharmaceutical composition comprising the bispecific antigen-binding molecule of any one of claims 1-37, and a pharmaceutically acceptable carrier or diluent.

43. A pharmaceutical composition comprising the bispecific antibody of any one of claims 38-41, and a pharmaceutically acceptable carrier or diluent.

44. A method for making a bispecific antigen-binding molecule of any one of claims 1-37 comprising: (a) introducing one or more nucleic acid molecules comprising nucleic acid sequences encoding the immunoglobulin chains of said bispecific antigen-binding molecule into a host cell; (b) culturing the host cell under conditions favorable to expression of the nucleic acid molecules; and (c) optionally, isolating the bispecific antigen-binding molecule or immunoglobulin chain from the host cell and / or medium in which the host cell is grown.

45. The method of claim 44, wherein the host cell is a Chinese hamster ovary (CHO) cell.

46. The method of claim 44 or 45, further comprising formulating the antigen-binding molecule as a pharmaceutical composition comprising an acceptable carrier.

47. An antigen-binding molecule or immunoglobulin chain which is a product of the method of claim 44 or 45.

48. A nucleic acid molecule comprising a nucleotide sequence encoding a bispecific antigen-binding molecule of any one of claims 1-37, or a set of nucleic acid molecules comprising nucleotide sequences encoding the HCVR of the first antigen-binding domain that specifically binds to human CD28, the HCVR of the second antigen-binding domain that specifically binds to human PD-L1 , and the LCVR of any one of claims 1-37.

49. An expression vector comprising the nucleic acid molecule of claim 48, or a set of expression vectors comprising the set of nucleic acid molecules of claim 48.

50. A host cell comprising the expression vector or set of expression vectors of claim 49.

51. The host cell of claim 50, wherein the host cell is a Chinese hamster ovary (CHO) cell.

52. A method of producing a bispecific antigen-binding molecule that binds to PD-L1 and CD28 comprising: (a) culturing the host cell of claim 50 under conditions favorable for production of the bispecific antigen-binding molecule; and (b) optionally, isolating the antigenbinding molecule or immunoglobulin chain from the host cell and / or medium in which the host cell is grown.

53. The method of claim 52, wherein the host is a CHO cell.

54. The method of claim 52 or 53 further comprising formulating the antigen-binding molecule as a pharmaceutical composition comprising an acceptable carrier.

55. An antigen-binding molecule or immunoglobulin chain which is a product of the method of claim 52 or 53.

56. A nucleic acid molecule comprising a nucleotide sequence encoding a bispecific antibody of any one of claims 38-41 , or a set of nucleic acid molecules comprising nucleotide sequences encoding the heavy chain of the first antigen-binding domain that specifically binds to human CD28, the heavy chain of the second antigen-binding domain that specifically binds to human PD-L1 , and the light chain of any one of claims 38-41.

57. An expression vector comprising the nucleic acid molecule of claim 56, or a set of expression vectors comprising the set of nucleic acid molecules of claim 56.

58. A host cell comprising the expression vector or set of expression vectors of claim 57.

59. The host cell of claim 58, wherein the host cell is a Chinese hamster ovary (CHO) cell.

60. A method of producing a bispecific antibody that binds to PD-L1 and CD28 comprising: (a) culturing the host cell of claim 58 under conditions favorable for production of the bispecific antibody; and (b) optionally, isolating the bispecific antibody from the host cell and / or medium in which the host cell is grown.

61. The method of claim 60, wherein the host is a CHO cell.

62. The method of claim 60 or 61 further comprising formulating the bispecific antibody as a pharmaceutical composition comprising an acceptable carrier.

63. An antibody which is a product of the method of claim 60 or 61 .

64. A method of inhibiting growth of a tumor in a subject, comprising administering an isolated bispecific antigen-binding molecule of any one of claims 1-37, or a bispecific antibody of any one of claims 38-41 , or a pharmaceutical composition of claim 42 or 43, to the subject.

65. The method of claim 64, wherein the tumor is esophageal carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, cervical squamous cell carcinoma, endometrial adenocarcinoma, bladder urothelial carcinoma, lung cancer, non-small cell lung cancer, colorectal cancer, rectal cancer, endometrial cancer, skin cancer, head & neck squamous cell carcinoma, brain cancer, glioblastoma multiforme, breast cancer, gastroesophageal cancer,gastroesophageal adenocarcinoma, hepatocellular carcinoma, prostate cancer, ovarian cancer, a B cell cancer, a T cell cancer, leukemia, pancreatic cancer, colon cancer, melanoma, basal cell carcinoma, cervical cancer, diffuse large B cell lymphoma, or multiple myeloma.

66. The method of claim 64 or 65, wherein the tumor expresses PD-L1.

67. The method of any one of claims 64-66, further comprising administering a second therapeutic agent or therapeutic regimen.

68. The method of claim 67, wherein the second therapeutic agent or therapeutic regimen comprises a chemotherapeutic drug, a DNA alkylator, an immunomodulator, a proteasome inhibitor, a histone deacetylase inhibitor, radiotherapy, surgery, a stem cell transplant, a bispecific antibody that interacts with a tumor associated antigen (TAA) and a T cell or immune cell antigen, an antibody drug conjugate, an oncolytic virus, a bispecific antibody conjugated to an anti-tumor agent, a VEGF inhibitor, a checkpoint inhibitor, a GITR agonist, a CD27 agonist, a 4-1 BB activator, a PD-1 inhibitor, a CTLA-4 inhibitor, an EGFR inhibitor, Ang2 inhibitor, a MUC16 inhibitor, a cancer vaccine, a cytokine, a modified IL2, a modified IL12, IL4 inhibitor, IL6 inhibitor, a corticosteroid, or combinations thereof.

69. The method of claim 68, wherein the T cell or immune cell antigen is CD3.

70. The method of claim 68 or 69, wherein the TAA is selected from the group consisting of AFP, ALK, BAGE proteins, BCMA, BIRC5 (survivin), BIRC7, [3-catenin, brc-abl, BRCA1 , BORIS, CA9, carbonic anhydrase IX, caspase-8, CALR, CCR5, CD19, CD20 (MS4A1), CD22, CD30, CD40, CDK4, CEA, CTLA4, cyclin-B1 , CYP1 B1 , EGFR, EGFRvlll, ErbB2 / Her2, ErbB3, ErbB4, ETV6-AML, EpCAM, EphA2, Fra-1 , FOLR1 , GAGE proteins (e.g., GAGE-1 , -2), GD2, GD3, GloboH, glypican-3, GM3, gp100, Her2, HLA / B-raf, HLA / k-ras, HLA / MAGE-A3, hTERT, LMP2, MAGE proteins (e.g., MAGE-1 , -2, -3, -4, -6, and -12), MART-1 , mesothelin, ML-IAP, Muc1, Muc2, Muc3, Muc4, Muc5, Muc16 (CA-125), MUM1 , NA17, NY-BR1 , NY-BR62, NY-BR85, NY- ESO1, 0X40, p15, p53, PAP, PAX3, PAX5, PCTA-1, PLAC1 , PRLR, FRAME, PSMA (FOLH1), RAGE proteins, Ras, RGS5, Rho, SART-1, SART-3, STEAP1, STEAP2, TAG-72, TGF-p, TMPRSS2, Thompson-nouvelle antigen (Tn), TRP-1 , TRP-2, tyrosinase, and uroplakin-3.

71. Use of the bispecific antigen-binding molecule of any one of claims 1-37, or a bispecific antibody of any one of claims 38-41 , or a pharmaceutical composition of claim 42 or 43, in the treatment of a tumor.

72. The use of claim 71 , wherein the tumor is esophageal carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, cervical squamous cell carcinoma, endometrial adenocarcinoma, bladder urothelial carcinoma, lung cancer, non-small cell lung cancer, colorectal cancer, rectal cancer, endometrial cancer, skin cancer, head & neck squamous cell carcinoma, brain cancer, glioblastoma multiforme, breast cancer, gastroesophageal cancer, gastroesophageal adenocarcinoma, hepatocellular carcinoma, prostate cancer, ovarian cancer, a B cell cancer, a T cell cancer, leukemia, pancreatic cancer, colon cancer, melanoma, basal cell carcinoma, cervical cancer, diffuse large B cell lymphoma, or multiple myeloma.

73. The use of claim 71 or 72, wherein the tumor expresses PD-L1 .

74. The use of any one of claims 71-73, wherein the antigen-binding molecule or pharmaceutical composition is for use in combination with a second therapeutic agent or therapeutic regimen that comprises a chemotherapeutic drug, a DNA alkylator, an immunomodulator, a proteasome inhibitor, a histone deacetylase inhibitor, radiotherapy, surgery, a stem cell transplant, a bispecific antibody that interacts with a tumor associated antigen (TAA) and a T cell or immune cell antigen, an antibody drug conjugate, an oncolytic virus, a bispecific antibody conjugated to an anti-tumor agent, a VEGF inhibitor, a checkpoint inhibitor, a GITR agonist, a CD27 agonist, a 4-1 BB activator, a PD-1 inhibitor, a CTLA-4 inhibitor, an EGFR inhibitor, Ang2 inhibitor, a MUC16 inhibitor, a cancer vaccine, a cytokine, a modified IL2, a modified I L12, IL4 inhibitor, IL6 inhibitor, a corticosteroid, or combinations thereof.

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