METHODS OF USING ANTI-PD-L1 ANTIBODIES AND THEIR USE TO ENHANCE T-CELL FUNCTION TO TREAT TUMOR IMMUNITY

1 . A method of treating a T-cell dysfunctional disorder resulting from tumor immunity comprising administering an effective amount of an 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:

(i) the HVR-H1 sequence is GFTFSX 1 SWIH (SEQ ID NO:1);

(ii) the HVR-H2 sequence is AWIX 2 PYGGSX 3 YYADSVKG (SEQ ID NO:2);

(iii) the HVR-H3 sequence is RHWPGGFDY, and (SEQ ID NO:3);

(b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:

(iv) the HVR-L1 sequence is RASQX 4 X 5 X 6 TX 7 X 8 A (SEQ ID NOs:8);

(v) the HVR-L2 sequence is SASX 9 LX 10 S (SEQ ID NOs:9);

(vi) the HVR-L3 sequence is QQX 11 X 12 X 13 X 14 PX 15 T (SEQ ID NOs:10);

wherein: X 1 is D or G; X 2 is S or L; X 3 is T or S; X 4 may be D or V; X 5 may be V or I; X 6 may be S or N; X 7 may be A or F; X 8 may be V or L; X 9 may be F or T; X 10 may be Y or A; X 11 may be Y, G, F, or S; X 12 may be L, Y, F or W; X 13 may be Y, N, A, T, G, F or I; X 14 may be H, V, P, T or I; X 15 may be A, W, R, P or T.

2 . The method of claim 1 wherein X 1 is D; X 2 is S and X 3 is T.

3 . The method of claim 1 , wherein X 4 =D, X 5 =V, X 6 =5, X 7 =A and X 8 =V, X 9 =F, and X 10 =Y, X 11 =Y, X 12 =L, X 13 =Y, X 14 =H and X 15 =A.

4 . The method of claim 1 , wherein X 1 =D, X 2 =S and X 3 =T, X 4 =D, X 5 =V, X 6 =S, X 7 =A and X 8 =V, X 9 =F, and X 10 =Y, X 11 =Y, X 12 =L, X 13 =Y, X 14 =H and X 15 =A.

5 . The method of claim 4 , wherein the encoded variable region heavy chain framework sequences are juxtaposed between the HVRs according to the formula: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4) and/or the encoded 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).

6 . The method of claim 5 , wherein the framework sequences are human.

7 . The method of claim 6 wherein the variable heavy chain framework sequences are VH subgroup III consensus framework.

8 . The method of claim 6 wherein the variable region light chain framework sequences are VL kappa I consensus framework.

9 . The method of claim 7 wherein one or more of the heavy chain framework sequences is the following:

(SEQ ID NO: 4)

HC-FR1 is EVQLVESGGGLVQPGGSLRLSCAAS;

(SEQ ID NO: 5)

HC-FR2 is WVRQAPGKGLEWV;

(SEQ ID NO: 6)

HC-FR3 is RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR;

(SEQ ID NO: 7)

HC-FR4 is WGQGTLVTVSA.

10 . The method of claim 8 wherein one or more of the light chain framework sequences is the following:

(SEQ ID NO: 11)

LC-FR1 is DIQMTQSPSSLSASVGDRVTITC;

(SEQ ID NO: 12)

LC-FR2 is WYQQKPGKAPKLLIY;

(SEQ ID NO: 13)

LC-FR3 is GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC,

and;

(SEQ ID NO: 14)

LC-FR4 is FGQGTKVEIKR.

11 . The method of claim 6 wherein:

(a) one or more of the heavy chain framework sequences is the following:

(SEQ ID NO: 4)

HC-FR1 is EVQLVESGGGLVQPGGSLRLSCAAS;

(SEQ ID NO: 5)

HC-FR2 is WVRQAPGKGLEWV;

(SEQ ID NO: 6)

HC-FR3 is RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR;

(SEQ ID NO: 7)

HC-FR4 is WGQGTLVTVSA;

and

(b) one or more of the light chain framework sequences is the following:

(SEQ ID NO: 11)

LC-FR1 is DIQMTQSPSSLSASVGDRVTITC;

(SEQ ID NO: 12)

LC-FR2 is WYQQKPGKAPKLLIY;

(SEQ ID NO: 13)

LC-FR3 is GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC,

and;

(SEQ ID NO: 14)

LC-FR4 is FGQGTKVEIKR.

12 . The method of claim 11 further comprising a human constant region.

13 . The method of claim 12 , wherein the constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.

14 . The method of claim 13 , wherein the constant region is IgG1.

15 . The method of claim 14 having reduced or minimal effector function.

16 . The method of claim 15 , wherein the minimal effector function results from an effector-less Fc mutation.

17 . The method of claim 16 , wherein the effector-less Fc mutation is N297A.

18 . The method of claim 16 , wherein the effector-less Fc mutation is D265A/N297A.

19 . The method of claim 15 , wherein the minimal effector function results from aglycosylation.

20 . A method of treating tumor immunity comprising administering to a patient a composition comprising a pharmaceutically-acceptable carrier and therapeutically effective amount of an 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 RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTL TISSLQPEDFATYYCQQYLYH PATFGQGTKVEIKR (SEQ ID NO:21).

21 . The method of claim 20 wherein the antibody further comprises a human constant region.

22 . The method of claim 21 , wherein the constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.

23 . The method of claim 22 , wherein the constant region is IgG1.

24 . The method of claim 23 having reduced or minimal effector function.

25 . The nucleic acid of claim 24 , wherein the minimal effector function results from an effector-less Fc mutation.

26 . The method of claim 25 , wherein the effector-less Fc mutation is N297A.

27 . The method of claim 25 , wherein the effector-less Fc mutation is D265A/N297A.

28 . The method of claim 24 , wherein the minimal effector function results from aglycosylation.

29 . The method of claims 20 - 28 , further comprising the administration of a vaccine.

30 . The method of claims 20 - 28 , further comprising the administration of a chemotherapeutic agent.

31 . The method of claims 20 - 28 , wherein the tumor immunity results from a cancer selected from the group consisting of breast, lung, colon, ovarian, melanoma, bladder, kidney, liver, saliary, stomach, gliomas, thyroid, thymic, epithelial, head and neck, gastric and pancreatic.

32 . The method of claim 30 , wherein the tumor immunity results from a cancer selected from the group consisting of breast, lung, colon, ovarian, melanoma, bladder, kidney, liver, saliary, stomach, gliomas, thyroid, thymic, epithelial, head and neck, gastric and pancreatic.

33 . The method of claim 30 , wherein the chemotherapeutic agent is an anti-VEGF antibody.

34 . The method of claim 30 , wherein the chemotherapeutic agent is FOLFOX.

35 . The method of claim 34 , wherein FOLFOX is a combination of oxaliplatin, 5-fluorouracil and leucovovin.

36 . The method of claim 30 , wherein the chemotherapeutic agent is oxaliplatin.

37 . The method of claim 30 , wherein the chemotherapeutic agent is a RAF inhibitor.