ANTI-PD-L1 ANTIBODIES AND THEIR USE TO ENHANCE T-CELL FUNCTION

• US 20100203056A1
• Filed: 12/08/2009
• Published: 08/12/2010
• Est. Priority Date: 12/09/2008
• Status: Active Grant

• Current Assignee: F Hoffmann-La Roche AG (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Cheung, Jeanne, Lehar, Sophie M., Maecker, Heather, Wu, Yan, Mariathasan, Sanjeev, Chiu, Henry, Irving, Bryan
• Granted Patent: US 8,217,149 B2
• Time in Patent Office: Days
• US Class Current: 424/139.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/1063 env, e.g. gp41, gp110/120, gp160, V3, PND, CD4 binding site
• CPC Class Codes: C07K 16/22 : against growth factors ; against growth regulators
• CPC Class Codes: C07K 16/28 : against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2827 : against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/30 : from tumour cells
• CPC Class Codes: C07K 16/3046 : Stomach, Intestines
• CPC Class Codes: C07K 2317/14 : Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/52 : Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2317/71 : Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/74 : Inducing cell proliferation
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• 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 application relates to anti-PD-L1 antibodies, nucleic acid encoding the same, therapeutic compositions thereof, and their use enhance T-cell function to upregulate cell-mediated immune responses and for the treatment of T cell dysfunctional disorders, including infection (e.g., acute and chronic) and tumor immunity.

Claims

1. An isolated heavy chain variable region polypeptide comprising an HVR-H1, HVR-H2 and HVR-H3 sequence, wherein:

2. The polypeptide of claim 1 wherein X₁ is D;

X₂ is S and X₃ is T.

3. The polypeptide of claim 1 further comprising variable region heavy chain framework sequences juxtaposed between the HVRs according to the formula:

(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4).

4. The polypeptide of claim 3 wherein the framework sequences are derived from human consensus framework sequences.

5. The polypeptide of claim 4 wherein the framework sequences are VH subgroup III consensus framework.

6. The polypeptide of claim 5 wherein one or more of the framework sequences is the following:

7. The isolated heavy chain polypeptide of claim 1 in combination with a variable region light chain comprising an HVR-L1, HVR-L2 and HVR-L3, wherein:

8. The polypeptide of claim 7 wherein X₄ is D;

X₅ is V;

X₆ is S;

X₇ is A;

X₈ is V;

X₉ is F;

X₁₀ is Y;

X₁₁ is Y;

X₁₂ is L;

X₁₃ is Y;

X₁₄ is H;

X₁₅ is A.

9. The polypeptide of claim 7 further comprising variable region light chain framework sequences juxtaposed between the HVRs according to the formula:

(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4).

10. The polypeptide of claim 9 wherein the framework sequences are derived from human consensus framework sequences.

11. The polypeptide of claim 10 wherein the framework sequences are VL kappa I consensus framework.

12. The polypeptide of claim 11 wherein one or more of the framework sequences is the following:

49. An isolated nucleic acid encoding the polypeptide of any of claims 1-11.

61. A vector comprising the nucleic acid of any of claims 49-60.

62. A host cell comprising the vector of claim 61.

63. The host cell of claim 62 which is eukaryotic.

64. The host cell of claim 63 which is mammalian.

65. The host cell of claim 64 which is a Chinese Hamster Ovary (CHO) cell.

66. The host cell of claim 62 which is prokaryotic.

67. The host cell of claim 66 which is E. coli.

68. A process for making an anti-PD-L1 antibody comprising culturing the host cell of any of claims 62-67 under conditions suitable for the expression of the vector encoding the anti-PD-L1 antibody or antigen binding fragment, and recovering the antibody or fragment.

13. An isolated anti-PD-L1 antibody or antigen binding fragment comprising a heavy chain and a light chain variable region sequence, wherein:

(a) the heavy chain comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further;

14. The antibody or antibody fragment of claim 13 wherein X₁ is D;

X₂ is S and X₃ is T.

15. The antibody or antibody fragment of claim 13, wherein X₄=D, X₅=V, X₆=S, X₇=A and X_g=V, X₉=F, and X₁₀=Y, X₁₁=Y, X₁₂=L, X₁₃=Y, X₁₄H and X₁₅=A.

16. The antibody or antibody fragment of claim 13, wherein X₁=D, X₂=S and X₃=T, X₄=D, X₅=V, X₆=S, X₇=A and X₈=V, X₉=F, and X₁₀=Y, X₁₁=Y, X₁₂=L, X₁₃=Y, X₁₄=H and X₁₅=A.

17. The antibody or antibody fragment of any of claims 13-16 further comprising:

(a) variable region heavy chain framework sequences juxtaposed between the HVRs according to the formula;

(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4), and

(b) variable region light chain framework sequences juxtaposed between the HVRs according to the formula;

(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4).

18. The antibody or antibody fragment of claim 17 wherein the framework sequences are derived from human consensus framework sequences.

19. The antibody or antibody fragment of claim 18 wherein the variable region heavy chain framework sequences are VH subgroup III consensus framework.

20. The antibody or antibody fragment of claim 19 wherein one or more of the framework sequences is the following:

21. The antibody or antibody fragment of claim 18 wherein the variable region light chain framework sequences are VL kappa I consensus framework.

22. The antibody or antibody fragment of claim 21 wherein one or more of the framework sequences is the following:

23. The antibody of or antibody fragment of claim 18 wherein:

(a) the variable heavy chain framework sequences are the following;

24. The antibody or antibody fragment of claim 23 further comprising a human constant region.

25. The antibody or antibody fragment of claim 24, wherein the constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.

26. The antibody of antibody fragment of claim 25 wherein the constant region is IgG1.

27. The antibody or antibody fragment of claim 23, further comprising murine constant region.

28. The antibody or antibody fragment of claim 27 wherein the constant region is selected from the group consisting of IgG1, IgG2A, IgG2B and IgG3.

29. The antibody or antibody fragment of claim 28, wherein the constant region is IgG2A.

30. The antibody or antibody fragment of claim 25 or 28 having reduced or minimal effector function.

31. The antibody or antibody fragment of claim 30, wherein the minimal effector function results from an effector-less Fc mutation.

32. The antibody or antibody fragment of claim 31, wherein the effector-less Fc mutation is N297A.

33. The antibody or antibody fragment of claim 31, wherein the effector-less Fc mutation is D265A/N297A.

34. The antibody or antibody fragment of claim 30, wherein the minimal effector function results from aglycosylation.

48. A composition comprising the anti-PD-L1 antibody or antigen binding fragment of any of claims 13-47 and at least one pharmaceutically-acceptable carrier.

69. An article of manufacture comprising the composition of claim 48 and at least one BNCA molecule.

70. An article of manufacture comprising the composition of claim 48 and at least one chemotherapeutic agent.

71. The article of manufacture according to claim 70, wherein the chemotherapeutic agent is gemcitabine.

72. An article of manufacture comprising the composition of claim 48 and at least one agonist to a positive costimulatory molecule.

73. The article of manufacture according to claim 72, further comprising a BNCA antagonist.

74. An article of manufacture comprising the composition of claim 48 and at least one antibiotic.

75. The article of manufacture according to claim 74, wherein the antibiotic is an anti-viral agent.

76. The article of manufacture according to claim 75, wherein anti-viral agent is a reverse transcriptase inhibitor.

77. The article of manufacture according to claim 76, wherein the reverse transcriptase inhibitor is a polymerase inhibitor.

78. The article of manufacture according to claim 75, wherein the anti-viral agent is a protease inhibitor.

79. An article of manufacture comprising the composition of claim 48 and at least one vaccine.

80. A method of enhacing T-cell function comprising administration of an effective amount of the composition of claim 48 to a dysfunctional T-cell.

81. A method of treating a T-cell dysfunctional disorder comprising administering a therapeutically effective amount of the composition of claim 48 to a patient suffering from a T-cell dysfunctional disorder.

82. The method of claim 81, wherein the T-cell dysfunctional disorder is infection.

83. The method of claim 82, wherein the infection is chronic.

84. The method of claim 81, wherein the T-cell dysfunctional disorder is tumor immunity.

85. The method of claim 83, therein the chronic infection is persistent.

86. The method of claim 83, wherein the chronic infection is latent.

87. The method of claim 83, wherein the chronic infection is slow.

88. The method of claim 82 wherein the infection results from a pathogen selected from the group consisting of bacteria, virus, fungi and protozoan.

89. The method of claim 88 wherein the pathogen is a bacteria and the method further comprises the administration of an anti-bacterial agent.

90. The method of claim 88, wherein the pathogen is virus and the method further comprises the administration of an anti-viral agent.

91. The method of claim 88, wherein the pathogen is a fungi and the method further comprises the administration of an anti-fungal agent.

92. The method of claim 88, wherein the pathogen is a protozoan and the method further comprising the administration of an anti-protozoan agent.

93. The method of claim 88, further comprising the administration of a vaccine.

94. The method of claim 84, wherein the method further comprising the application of a treatment regimen selected from the group consisting of:

radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, angiogenesis inhibiton and palliative care.

95. The method of claim 84, wherein the tumor immunity results from a cancer selected from the group consisting of:

breast, lung, colon, ovarian, melanoma, bladder, kidney, liver, salivary, stomach, gliomas, thyroid, thymic, epithelial, head and neck cancers, gastric and pancreatic cancer.

35. An antibody or antigen binding fragment comprising a heavy chain and a light chain variable region sequence, wherein:

(a) the heavy chain comprises an HVR-H1, HVR-H2 and an HVR-H3, having at least 85% overall sequence identity to GFTFSDSWIH (SEQ ID NO;

15), AWISPYGGSTYYADSVKG (SEQ ID NO;

16) and RHWPGGFDY (SEQ ID NO;

3), respectively, and

(b) the light chain comprises an HVR-L1, HVR-L2 and an HVR-L3, having at least 85% overall sequence identity to RASQDVSTAVA (SEQ ID NO;

17), SASFLYS (SEQ ID NO;

18) and QQYLYHPAT (SEQ ID NO;

19), respectively.

36. The antibody or antibody fragment of claim 35, wherein the sequence identity is at least 90%.

37. The antibody or antibody fragment of claims 36 further comprising:

(a) variable region heavy chain (VH) framework sequences juxtaposed between the HVRs according to the formula;

(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4), and

(b) variable region light chain (VL) framework sequences juxtaposed between the HVRs according to the formulat;

(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4).

38. The antibody or antibody fragment of claim 37, further comprising a VH and VL framework region derived from a human consensus sequence.

39. The antibody or antibody fragment of claim 38, wherein the VH framework sequence is derived from a Kabat subgroup I, II, or III sequence.

40. The antibody or antibody fragment of claim 39, wherein the VH framework sequence is a Kabat subgroup III consensus framework sequence.

41. The antibody or antibody fragment of claim 40 wherein the VH framework sequences are the following:

42. The antibody or antibody fragment of claim 38, wherein the VL framework sequence is derived from a Kabat kappa I, II, III or IV subgroup sequence.

43. The antibody or antibody fragment of claim 42 wherein the VL framework sequence is a Kabat kappa I consensus framework sequence.

44. The antibody or antibody fragment of claim 43 wherein the VL framework sequences are the following:

45. An isolated anti-PD-L1 antibody or antigen binding fragment comprising a heavy chain and a light chain variable region sequence, wherein:

(a) the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence;

EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPG KGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDT AVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO;

20), and

(b) the light chain sequence has at least 85% sequence identity to the light chain sequence;

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGK APKWYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYH PATFGQGTKVEIKR (SEQ ID NO;

21).

46. The antibody or antigen binding fragment of claim 45, wherein the sequence identity is at least 90%.

47. An isolated anti-PD-L1 antibody or antigen binding fragment comprising a heavy chain and light chain variable region sequence, wherein:

(a) the heavy chain comprises the sequence;

EVQLVESGGGLVQPGGSLRLS CAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVS A (SEQ ID NO;

20), and

(b) the light chain comprises the sequence;

DIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTL TISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO;

21).

50. An isolated nucleic acid encoding a light chain or a heavy chain variable sequence of an anti-PD-L1 antibody or antigen binding fragment, wherein:

(a) the heavy chain further comprises and HVR-H1, HVR-H2 and an HVR-H3 sequence having at least 85% sequence identity to GFTFSDSWIH (SEQ ID NO;

15), AWISPYGGSTYYADSVKG (SEQ ID NO;

16) and RHWPGGFDY (SEQ ID NO;

3), respectively, or

(b) the light chain further comprises an HVR-L1, HVR-L2 and an HVR-L3 sequence having at least 85% sequence identity to RASQDVSTAVA (SEQ ID NO;

17), SASFLYS (SEQ ID NO;

18) and QQYLYHPAT (SEQ ID NO;

19), respectively.

51. The nucleic acid of claim 50, wherein sequence identity is 90%.

52. The nucleic acid of claim 50, wherein the anti-PD-L1 antibody further comprises a VL and a VH framework region derived from a human consensus sequence.

53. The nucleic acid of claim 52, wherein the VH sequence is derived from a Kabat subgroup I, II, or III sequence.

54. The nucleic acid of claim 52, wherein the VL sequence is derived from a Kabat kappa I, II, III or IV subgroup sequence.

55. The nucleic acid of claim 50, wherein the anti-PD-L1 antibody comprises a constant region derived from a murine antibody.

56. The nucleic acid of claim 50, wherein the anti-PD-L1 antibody comprises a constant region derived from a human antibody.

57. The nucleic acid of claim 56, wherein the constant region is IgG1.

58. The nucleic acid of claim 57, having reduced or minimal effector function.

59. The nucleic acid of claim 58, wherein the minimal effector function results from an effector-less Fc mutation.

60. The nucleic acid of claim 59, wherein the effector-less Fc mutation is N297A.