Nucleic acids encoding monoclonal antibodies to programmed death ligand 1 (PD-L1)

• US 8,383,796 B2
• Filed: 04/21/2011
• Issued: 02/26/2013
• 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., Selby, Mark J., Wang, Changyu, Srinivasan, Mohan, Passmore, David B., Huang, Haichun, Chen, Haibin
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US13/091,936
• Publication Number:
  US 20110209230A1
• Time in Patent Office: 677 Days
• Field of Search: None
• US Class Current: 536/23.1
• 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 nucleic acid encoding a heavy chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising CDR1, CDR2, and CDR3 domains, wherein the CDR3 domain comprises

(a) amino acids having the sequence set forth in SEQ ID NO:

41 and conservative modifications thereof;

(b) amino acids having the sequence set forth in SEQ ID NO;

42 and conservative modifications thereof;

(c) amino acids having the sequence set forth in SEQ ID NO;

43 and conservative modifications thereof;

(d) amino acids having the sequence set forth in SEQ ID NO;

44 and conservative modifications thereof;

(e) amino acids having the sequence set forth in SEQ ID NO;

45 and conservative modifications thereof;

(f) amino acids having the sequence set forth in SEQ ID NO;

46 and conservative modifications thereof,

(g) amino acids having the sequence set forth in SEQ ID NO;

47 and conservative modifications thereof;

(h) amino acids having the sequence set forth in SEQ ID NO;

48 and conservative modifications thereof;

(i) amino acids having the sequence set forth in SEQ ID NO;

49 and conservative modifications thereof;

or

(j) amino acids having the sequence set forth in SEQ ID NO;

50 and conservative modifications thereof.

2. The isolated nucleic acid of claim 1, wherein the CDR3 and CDR2 domains are:

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

41 and conservative modifications thereof, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

31 and conservative modifications thereof;

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

42 and conservative modifications thereof, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

32 and conservative modifications thereof;

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

43 and conservative modifications thereof, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

33 and conservative modifications thereof;

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

44 and conservative modifications thereof, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

34 and conservative modifications thereof;

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

45 and conservative modifications thereof, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

35 and conservative modifications thereof;

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

46 and conservative modifications thereof, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

36 and conservative modifications thereof;

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

47 and conservative modifications thereof, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

37 and conservative modifications thereof;

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

48 and conservative modifications thereof, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

38 and conservative modifications thereof;

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

49 and conservative modifications thereof, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

39 and conservative modifications thereof;

or

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

50 and conservative modifications thereof, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

40 and conservative modifications thereof.

3. The isolated nucleic acid of claim 2, wherein the CDR3, CDR2, and CDR1 domains are:

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

41 and conservative modifications thereof, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

31 and conservative modifications thereof, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

21 and conservative modifications thereof;

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

42 and conservative modifications thereof, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

32 and conservative modifications thereof, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

22 and conservative modifications thereof;

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

43 and conservative modifications thereof, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

33 and conservative modifications thereof, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

23 and conservative modifications thereof;

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

44 and conservative modifications thereof, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

34 and conservative modifications thereof, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

24 and conservative modifications thereof;

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

45 and conservative modifications thereof, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

35 and conservative modifications thereof and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

25 and conservative modifications thereof;

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

46 and conservative modifications thereof, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

36 and conservative modifications thereof and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

26 and conservative modifications thereof;

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

47 and conservative modifications thereof, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

37 and conservative modifications thereof, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

27 and conservative modifications thereof;

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

48 and conservative modifications thereof, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

38 and conservative modifications thereof, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

28 and conservative modifications thereof;

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

49 and conservative modifications thereof, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

39 and conservative modifications thereof, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

29 and conservative modifications thereof; and

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

50 and conservative modifications thereof, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

40 and conservative modifications thereof, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

30 and conservative modifications thereof.

4. The isolated nucleic acid of claim 1, further encoding a light chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, wherein the light chain variable region comprises CDR1, CDR2, and CDR3 domains, and wherein the heavy chain variable region and light chain variable region CDR3 domains are:

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

41 and conservative modifications thereof, 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 conservative modifications thereof, 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 conservative modifications thereof, 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 conservative modifications thereof, 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 conservative modifications thereof, 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 conservative modifications thereof, 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 conservative modifications thereof, 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 conservative modifications thereof, 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 conservative modifications thereof, 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 conservative modifications thereof, and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

80 and conservative modifications thereof.

5. The isolated nucleic acid of claim 4, wherein the light chain variable region CDR3 and CDR2 domains are:

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

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

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

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

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

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

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

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

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

79 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;

or

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

80 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.

6. The isolated nucleic acid of claim 5, wherein the light chain variable region CDR3, CDR2, and CDR1 domains are:

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

71 and conservative modifications thereof, a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

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

72 and conservative modifications thereof, a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

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

73 and conservative modifications thereof, a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

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

74 and conservative modifications thereof, a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

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

75 and conservative modifications thereof, a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

65 and conservative modifications thereof, 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 light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

76 and conservative modifications thereof, a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

66 and conservative modifications thereof, 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 light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

77 and conservative modifications thereof, a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

67 and conservative modifications thereof, 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 light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

78 and conservative modifications thereof, a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

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

79 and conservative modifications thereof, a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

69 and conservative modifications thereof, and light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

59 and conservative modifications thereof;

or

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

80 and conservative modifications thereof, a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

70 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.

7. An isolated nucleic acid encoding an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising:

(a) the nucleic acid of claim 6; and

(b) one or more nucleic acids encoding one or more constant domains of said monoclonal antibody or antigen-binding portion thereof, operatively linked together.

14. An expression vector comprising the nucleic acid of claim 1 or claim 4.

15. An isolated host cell expressing a polypeptide or glycoprotein encoded by the nucleic acid of claim 1 or claim 4.

16. A transgenic mouse comprising the host cell of claim 15, wherein the mouse expresses a polypeptide encoded by the nucleic acid.

17. A process for producing an anti-PD-L1 antibody, or antigen-binding portion thereof, comprising culturing a host cell transfected with the expression vector of claim 14.

8. An isolated nucleic acid encoding a heavy chain variable region and a light chain variable region of an anti-PD-1,1 monoclonal antibody, or antigen-binding portion thereof, said variable regions comprising:

(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;

or

(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.

9. An isolated nucleic acid encoding a heavy chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising amino acids having the sequence of:

SEQ ID NO;

1, SEQ ID NO;

2, SEQ ID NO;

3, SEQ ID NO;

4, SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

7, SEQ ID NO;

8, SEQ ID NO;

9 or SEQ ID NO;

10.

20. The isolated nucleic acid of claim 9 encoding a heavy chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising amino acids having the sequence of SEQ ID NO:

1.

21. The isolated nucleic acid of claim 9, encoding a heavy chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising amino acids having the sequence of SEQ ID NO:

2.

22. The isolated nucleic acid of claim 9, encoding a heavy chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising amino acids having the sequence of SEQ ID NO:

3.

10. An isolated nucleic acid encoding a light chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising amino acids having the sequence of:

SEQ ID NO;

11, SEQ ID NO;

12, SEQ ID NO;

13, SEQ ID NO;

14, SEQ ID NO;

15, SEQ ID NO;

16, SEQ ID NO;

17, SEQ ID NO;

18, SEQ ID NO;

19 or SEQ ID NO;

20.

23. The isolated nucleic acid of claim 10, encoding a light chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising amino acids having the sequence of:

SEQ ID NO;

11.

24. The isolated nucleic acid of claim 10, encoding a light chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising amino acids having the sequence of;

SEQ ID NO;

12.

25. The isolated nucleic acid of claim 10, encoding a light chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising amino acids having the sequence of:

SEQ ID NO;

13.

11. An isolated nucleic acid encoding a heavy chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, said nucleic acid comprising nucleotides having the sequence of:

SEQ ID NO;

81, SEQ ID NO;

82, SEQ ID NO;

83, SEQ ID NO;

84, SEQ ID NO;

85, SEQ ID NO;

86, SEQ ID NO;

87, SEQ ID NO;

88, SEQ ID NO;

89 or SEQ ID NO;

90.

12. An isolated nucleic acid encoding a light chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, said nucleic acid comprising nucleotides having the sequence of:

SEQ ID NO;

91, SEQ ID NO;

92, SEQ ID NO;

93, SEQ ID NO;

94, SEQ ID NO;

95, SEQ ID NO;

96, SEQ ID NO;

97, SEQ ID NO;

98, SEQ ID NO;

99 or SEQ ID NO;

100.

13. An isolated nucleic acid encoding a 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, or antigen-binding portion thereof, specifically binds to PD-L1.

18. An isolated nucleic acid encoding a heavy chain variable region of an anti-PD-L1monoclonal antibody, or antigen-binding portion thereof, comprising CDR1, CDR2, and CDR3domains, wherein the CDR1, CDR2, and CDR3 domains are:

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

41, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

31, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

21;

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

42, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

32, and a CDR1comprising amino acids having the sequence set forth in SEQ ID NO;

22;

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

43, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

33, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

23;

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

44, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

34, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

24;

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

45, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

35, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

25;

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

46, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

36, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

26;

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

47, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

37, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

27;

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

48, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

38, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

28;

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

49, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

39, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

29;

or

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

50, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

40, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

30.

26. The isolated nucleic acid of claim 18, encoding a heavy chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:

41, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

31, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

21.

27. The isolated nucleic acid of claim 18, encoding a heavy chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:

42, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

32, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

22.

28. The isolated nucleic acid of claim 18, encoding a heavy chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:

43, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

33, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

23.

19. An isolated nucleic acid encoding a light chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising CDR1, CDR2, and CDR3 domains, wherein the CDR3, CDR2, and CDR1 domains are:

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

71, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

61, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

51;

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

72, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

62, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

52;

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

73, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

63, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

53;

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

74, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

64, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

54;

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

75, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

65, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

55;

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

76, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

66, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

56;

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

77, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

67, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

57;

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

78, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

68, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

58;

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

79, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

69, and CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

59;

or

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

80, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

70, and CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

60.

29. The isolated nucleic acid of claim 19, encoding a light chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:

71, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

61, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

51 .

30. The isolated nucleic acid of claim 19, encoding a light chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:

72, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

62, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

52.

31. The isolated nucleic acid of claim 19, encoding a light chain variable region of an anti-PD-L1 monoclonal antibody, or antigen-binding portion thereof, comprising a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:

73, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

63, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

53.