Human monoclonal antibodies to programmed death ligand 1 (PD-L1)

• US 7,943,743 B2
• Filed: 06/30/2006
• Issued: 05/17/2011
• Est. Priority Date: 07/01/2005
• Status: Active Grant

• Current Assignee: ER Squibb & Sons LLC (Bristol-Myers Squibb Company)
• Original Assignee: Medarex Incorporated (Bristol-Myers Squibb Company)
• Inventors: Korman, Alan J., Chen, Haibin, Wang, Changyu, Selby, Mark J., Huang, Haichun, Srinivasan, Mohan, Passmore, David B.
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US11/917,727
• Publication Number:
  US 20090055944A1
• Time in Patent Office: 1,782 Days
• Field of Search: None
• US Class Current: 530/388.15
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/6817 Toxins
• CPC Class Codes: A61K 47/6825 Ribosomal inhibitory proteins, i.e. RIP-I or RIP-II, e.g. Pap, gelonin or dianthin
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/04 Amoebicides
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 33/10 : Anthelmintics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/28 : against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2803 : against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 16/2827 : against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/41 : Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/74 : Inducing cell proliferation
• CPC Class Codes: C07K 2317/75 : Agonist effect on antigen
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/77 : Internalization into the cell
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present disclosure provides isolated monoclonal antibodies, particularly human monoclonal antibodies that specifically bind to PD-L1 with high affinity. Nucleic acid molecules encoding the antibodies of this disclosure, expression vectors, host cells and methods for expressing the antibodies of this disclosure are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. The disclosure also provides methods for detecting PD-L1, as well as methods for treating various diseases, including cancer and infectious diseases, using anti-PD-L1 antibodies.

Claims

1. An isolated human monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion thereof cross-competes for binding to PD-L1 with a reference antibody or reference antigen-binding portion thereof comprising:

(a) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

1 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

11;

(b) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

2 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

12;

(c) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

3 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

13;

(d) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

4 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

14;

(e) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

5 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

15;

(f) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

6 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

16;

(g) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

7 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

17;

(h) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

8 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

18;

(i) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

9 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

19;

or

(j) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

10 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

20.

2. The antibody or antigen-binding portion thereof of claim 1, wherein the human heavy chain variable region comprises amino acids having the sequence set forth in SEQ ID NO:

1 and the human light chain variable region comprises amino acids having the sequence set forth in SEQ ID NO;

11.

3. The antibody or antigen-binding portion thereof of claim 1, wherein the human heavy chain variable region comprises amino acids having the sequence set forth in SEQ ID NO:

2 and the human light chain variable region comprises amino acids having the sequence set forth in SEQ ID NO;

12.

4. The antibody or antigen-binding portion thereof of claim 1, wherein the human heavy chain variable region comprises amino acids having the sequence set forth in SEQ ID NO:

3 and the human light chain variable region comprises amino acids having the sequence set forth in SEQ ID NO;

13.

5. The antibody of claim 1, wherein the antibody binds to human PD-L1 with a K_D of 5×

10<sup>−

9</sup> M or less.

6. The antibody of claim 1, wherein the antibody binds to human PD-L1 with a K_D of 2×

10<sup>−

9</sup> M or less.

21. A composition comprising the antibody, or antigen-binding portion thereof, of any one of claims 1, 13, and 17, and a pharmaceutically acceptable carrier.

22. An immunoconjugate comprising the antibody, or antigen-binding portion thereof, of any one of claims 1, 13, and 17, linked to a therapeutic agent.

23. The immunoconjugate of claim 22, wherein the therapeutic agent is a cytotoxin or a radioactive isotope.

24. A bispecific molecule comprising the antibody, or antigen-binding portion thereof, of any one of claims 1, 13, and 17, linked to a second functional moiety having a different binding specificity than said antibody, or antigen binding portion thereof.

25. The antibody or antigen-binding portion thereof of any one of claims 1, 13, and 17 wherein the antibody is IgG4 isotype.

7. An isolated human monoclonal antibody, or an antigen-binding portion thereof, comprising:

(a) a heavy chain variable region that comprises amino acids having a sequence derived from a human V_H 1-18 germline sequence; and

(b) a light chain variable region that comprises amino acids having a sequence derived from a human V_K L6 germline sequence;

wherein the antibody specifically binds to PD-L1.

8. An isolated human monoclonal antibody, or an antigen-binding portion thereof, comprising:

(a) a heavy chain variable region that comprises amino acids having a sequence derived from a human V_H 1-69 germline sequence; and

(b) a light chain variable region that comprises amino acids having a sequence derived from a human V_K L6 germline sequence;

wherein the antibody specifically binds to PD-L1.

9. An isolated human monoclonal antibody, or an antigen-binding portion thereof, comprising:

(a) a heavy chain variable region that comprises amino acids having a sequence derived from a human V_H 1-3 germline sequence; and

(b) a light chain variable region that comprises amino acids having a sequence derived from a human V_K L15 germline sequence;

wherein the antibody specifically binds to PD-L1.

10. An isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains;

and a light chain variable region that comprises CDR1, CDR2, and CDR3 domains, wherein the heavy chain variable region and light chain variable region CDR3 domains are selected from the group consisting of;

(a) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

41; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

71 and conservative modifications thereof;

(b) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

42; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

72 and conservative modifications thereof;

(c) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

43; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

73 and conservative modifications thereof;

(d) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

44; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

74 and conservative modifications thereof;

(e) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

45; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

75 and conservative modifications thereof;

(f) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

46; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

76 and conservative modifications thereof;

(g) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

47; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

77 and conservative modifications thereof;

(h) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

48; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

78 and conservative modifications thereof;

(i) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

49; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

79 and conservative modifications thereof; and

(j) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

50; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

80 and conservative modifications thereof;

wherein the antibody specifically binds to human PD-L1.

11. The antibody or antigen-binding portion thereof of claim 10, wherein the heavy chain variable region and light chain variable region CDR2 domains are selected from the group consisting of:

(a) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

31 and conservative modifications thereof; and

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

61 and conservative modifications thereof;

(b) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

32 and conservative modifications thereof; and

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

62 and conservative modifications thereof;

(c) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

33 and conservative modifications thereof; and

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

63 and conservative modifications thereof;

(d) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

34 and conservative modifications thereof; and

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

64 and conservative modifications thereof;

(e) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

35 and conservative modifications thereof; and

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

65 and conservative modifications thereof;

(f) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

36 and conservative modifications thereof; and

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

66 and conservative modifications thereof;

(g) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

37 and conservative modifications thereof; and

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

67 and conservative modifications thereof;

(h) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

38 and conservative modifications thereof; and

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

68 and conservative modifications thereof;

(i) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

39 and conservative modifications thereof; and

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

69 and conservative modifications thereof; and

(j) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

40 and conservative modifications thereof; and

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

70 and conservative modifications thereof.

12. The antibody or antigen-binding portion thereof of claim 11, wherein the heavy chain variable region and light chain variable region CDR1 domains are selected from the group consisting of:

(a) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

21 and conservative modifications thereof; and

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

51 and conservative modifications thereof;

(b) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

22 and conservative modifications thereof; and

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

52 and conservative modifications thereof;

(c) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

23 and conservative modifications thereof; and

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

53 and conservative modifications thereof;

(d) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

24 and conservative modifications thereof; and

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

54 and conservative modifications thereof;

(e) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

25 and conservative modifications thereof;

at and a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

55 and conservative modifications thereof;

(f) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

26 and conservative modifications thereat and a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

56 and conservative modifications thereof;

(g) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

27 and conservative modifications thereof;

at and a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

57 and conservative modifications thereof;

(h) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

28 and conservative modifications thereof; and

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

58 and conservative modifications thereof;

(i) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

29 and conservative modifications thereof; and

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

59 and conservative modifications thereof; and

(j) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

30 and conservative modifications thereof; and

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

60 and conservative modifications thereof.

13. An isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains;

and a light chain variable region that comprises CDR1, CDR2, and CDR3 domains, wherein the heavy chain variable region and light chain variable region CDR1, CDR2, and CDR3 domains are selected from the group consisting of;

(a) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

21;

a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

31;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

41;

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

51;

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

61; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

71;

(b) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

22;

a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

32;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

42;

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

52;

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

62; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

72;

(c) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

23;

a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

33;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

43;

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

53;

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

63; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

73;

(d) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

24;

a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

34;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

44;

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

54;

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

64; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

74;

(e) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

25;

a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

35;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

45;

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

55;

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

65; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

75;

(f) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

26;

a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

36;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

46;

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

56;

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

66; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

76;

(g) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

27;

a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

37;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

47;

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

57;

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

67; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

77;

(h) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

28;

a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

38;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

48;

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

58;

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

68; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

78;

(i) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

29;

a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

39;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

49;

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

59;

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

69; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

79; and

(j) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

30;

a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

40;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

50;

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

60;

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

70; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

80;

wherein the antibody specifically binds to PD-L1.

14. The antibody or antigen-binding portion thereof of claim 13, which comprises:

(a) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

21;

(b) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

31;

(c) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

41;

(d) a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

51;

(e) a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

61; and

(f) a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

71.

15. The antibody or antigen-binding portion thereof of claim 13, which comprises:

(a) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

22;

(b) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

32;

(c) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

42;

(d) a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

52;

(e) a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

62; and

(f) a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

72.

16. The antibody or antigen-binding portion thereof of claim 13, which comprises:

(a) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

23;

(b) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

33;

(c) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

43;

(d) a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

53;

(e) a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

63; and

(f) a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

73.

17. An isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and light chain variable region are selected from the group consisting of:

(a) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

1; and

a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

11;

(b) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

2; and

a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

12;

(c) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

3; and

a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

13;

(d) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

4; and

a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

14;

(e) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

5; and

a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

15;

(f) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

6; and

a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

16;

(g) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

7; and

a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

17;

(h) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

8; and

a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

18;

(i) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

9; and

a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

19; and

(j) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

10; and

a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

20;

wherein the antibody specifically binds to PD-L1.

18. The antibody or antigen-binding portion thereof of claim 17, which comprises:

(a) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

1; and

(b) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

11.

19. The antibody or antigen-binding portion thereof of claim 17, which comprises:

(a) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

2; and

(b) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

12.

20. The antibody or antigen-binding portion thereof of claim 17, which comprises:

(a) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

3; and

(b) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO;

13.

26. An isolated human monoclonal antibody, or an antigen-binding portion thereof, comprising:

(a) a heavy chain variable region that comprises amino acids having a sequence derived from a human V_H 1-69 germline sequence; and

a light chain variable region that comprises amino acids having a sequence derived from a human V_K A27 germline sequence;

(b) a heavy chain variable region that comprises amino acids having a sequence derived from a human V_H 3-9 germline sequence; and

a light chain variable region that comprises amino acids having a sequence derived from a human V_K L15 germline sequence;

or

(c) a heavy chain variable region that comprises amino acids having a sequence that is derived from a human V_H 3-9 germline sequence; and

a light chain variable region that comprises amino acids having a sequence derived from a human V_K L18 germline sequence;

wherein the antibody specifically binds to PD-L1.