Anti-PD-L1 antibodies, compositions and articles of manufacture

• US 8,217,149 B2
• Filed: 12/08/2009
• Issued: 07/10/2012
• 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: Irving, Bryan, Chiu, Henry, Maecker, Heather, Mariathasan, Sanjeev, Lehar, Sophie M., Wu, Yan, Cheung, Jeanne
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US12/633,339
• Publication Number:
  US 20100203056A1
• Time in Patent Office: 945 Days
• Field of Search: None
• US Class Current: 530/387.1
• 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 that specifically binds to PD-L1 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 human.

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, human.

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:

13. An isolated anti-PD-L1 antibody or antigen binding fragment thereof, wherein the antibody or antibody fragment comprises 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 X₈=V, X₉=F, and X₁₀=Y, X₁₁=Y, X₁₂=L, X₁₃=Y, X₁₄=H 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 claim 14 further wherein the antibody or antibody fragment comprises:

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).

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

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 15 further wherein the antibody comprises:

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).

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

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

24. The antibody of or antibody fragment of claim 16 wherein the antibody or antibody fragment comprises:

(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);

wherein the variable heavy chain framework sequences are the following;

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

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

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

28. The antibody or antibody fragment of claim 24, further comprising murine constant region.

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

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

31. The antibody or antibody fragment of claim 26 having reduced or minimal effector function.

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

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

34. The antibody or antibody fragment of claim 32, wherein the effector-less Fc mutation is D265A/N297A.

35. The antibody or antibody fragment of claim 31, wherein the minimal effector function results from aglycosylation.

37. The antibody or antibody fragment of claim 29 having reduced or minimal effector function.

38. The antibody or antibody fragment of claim 37, wherein the minimal effector function results from an effector-less Fc mutation.

39. The antibody or antibody fragment of claim 38, wherein the effector-less Fc mutation is N297A.

40. The antibody or antibody fragment of claim 38, wherein the effector-less Fc mutation is D265A/N297A.

41. The antibody or antibody fragment of claim 37, wherein the minimal effector function results from aglycosylation.

50. A composition comprising the anti-PD-L1 antibody or antigen binding fragment of any of claim 13-35, 36 or 21-49 and at least one pharmaceutically-acceptable carrier.

51. An article of manufacture comprising the composition of claim 50 and at least one chemotherapeutic agent.

52. The article of manufacture according to claim 51, wherein the chemotherapeutic agent is gemcitabine.

53. An article of manufacture comprising the composition of claim 50, and at least one B7-family costimulatory molecule.

54. An article of manufacture comprising the composition of claim 50 and at least one antibiotic.

55. The article of manufacture according to claim 54, wherein the antibiotic is an anti-viral agent.

56. The article of manufacture according to claim 55, wherein anti-viral agent is a reverse transcriptase inhibitor.

57. The article of manufacture according to claim 56, wherein the reverse transcriptase inhibitor is a polymerase inhibitor.

58. The article of manufacture according to claim 55, wherein the anti-viral agent is a protease inhibitor.

59. An article of manufacture comprising the composition of claim 50 and at least one vaccine.

60. An article of manufacture comprising the composition of claim 50.

61. The article of manufacture of claim 51, wherein the chemotherapeutic agent is an anti-VEGF antibody.

36. An isolated anti-PD-L1 antibody or antigen binding fragment thereof, wherein the antibody or antibody fragment comprises 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 RASQDVSTAVAWYQQKPGKAPKWYSASFLYSGVPSRFSGSGSGTDFTL TISSLQPEDFATYYCQQYLYH PATFGQGTKVEIKR (SEQ ID NO;

21).

42. The antibody or antibody fragment of claim 36 further comprising a human constant region.

43. The antibody or antibody fragment of claim 42, wherein the constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.

44. The antibody or antibody fragment of claim 43, wherein the constant region is IgG1.

45. The antibody or antibody fragment of claim 44 having reduced or minimal effector function.

46. The antibody or antibody fragment of claim 45, wherein the minimal effector function results from an effector-less Fc mutation.

47. The antibody or antibody fragment of claim 46, wherein the effector-less Fc mutation is N297A.

48. The antibody or antibody fragment of claim 46, wherein the effector-less Fc mutation is D265A/N297A.

49. The antibody or antibody fragment of claim 45, wherein the minimal effector function results from aglycosylation.