Anti-PD-L1 antibodies and uses thereof

1. A method of treating cancer comprising administering to a subject in need thereof an effective amount of an anti-PD-L1 antibody which induces antibody dependent cell-mediated cytotoxicity (ADCC), wherein the anti-PD-L1 antibody comprises:

a light chain variable region; and

a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3 sequences, wherein:

(a)

(SEQ ID NO: 1)

the HVR-H1 sequence is X 1 YX 2 MX 3 ;

(b)

(SEQ ID NO: 2)

the HVR-H2 sequence is SIYPSGGX 4 TFYADX 5 VKG;

and

(c)

(SEQ ID NO: 3)

the HVR-H3 sequence is IKLGTVTTVX 6 Y;

and further wherein:

X 1 is K, R, T, Q, G, A, W, M, I or S;

X 2 is V, R, K, L, M or I;

X 3 is H, T, N, Q, A, V, Y, W, F or M;

X 4 is F or I;

X 5 is S or T; and

X 6 is E or D.

2. The method of claim 1 , wherein the constant region of the anti-PD-L1 antibody is IgG1.

3. The method of claim 1 , wherein:

(a) X 1 is M, I or S; X 2 is R, K, L, M or I; X 3 is F or M; X 4 is F or I; X 5 is S or T; and X 6 is E or D;

(b) X 1 is M, I or S; X 2 is L, M or I; X 3 is F or M; X 4 is I; X 5 is S or T; and X 6 is D; or

(c) X 1 is S; X 2 is I; X 3 is M; X 4 is I; X 5 is T; and X 6 is D.

4. The method of claim 1 , wherein the heavy chain variable region comprises heavy chain framework sequences HC-FR1, HC-FR2, HC-FR3 and HC-FR4 interposed between the HVRs, thus forming a sequence of the formula: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4).

5. The method of claim 4 , wherein one or more of the heavy chain framework sequences is selected from:

(a)

(SEQ ID NO: 4)

HC-FR1 is EVQLLESGGGLVQPGGSLRLSCAASGFTFS;

(b)

(SEQ ID NO: 5)

HC-FR2 is WVRQAPGKGLEWVS;

(c)

(SEQ ID NO: 6)

HC-FR3 is RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR;

or

(d)

(SEQ ID NO: 7)

HC-FR4 is WGQGTLVTVSS.

6. The method of claim 1 , wherein the light chain variable region comprises HVR-L1, HVR-L2 and HVR-L3 sequences, wherein:

(a)

(SEQ ID NO: 8)

the HVR-L1 sequence is TGTX 7 X 8 DVGX 9 YNYVS;

(b)

(SEQ ID NO: 9)

the HVR-L2 sequence is X 10 VX 11 X 12 RPS;

and

(c)

(SEQ ID NO: 10)

the HVR-L3 sequence is SSX 13 TX 14 X 15 X 16 X 17 RV;

and further wherein:

X 7 is N or S;

X 8 is T, R or S;

X 9 is A or G;

X 10 is E or D;

X 11 is I, N or S;

X 12 is D, H or N;

X 13 is F or Y;

X 14 is N or S;

X 15 is R, T or S;

X 16 is G or S; and

X 17 is I or T.

7. The method of claim 6 , wherein:

(a) X 7 is N or S; X 8 is T, R or S; X 9 is A or G; X 10 is E or D; X 11 is N or S; X 12 is NT; X 13 is F or Y; X 14 is S; X 15 is S; X 16 is G or S; and X 17 is T; or

(b) X 7 is S; X 8 is S; X 9 is G; X 10 is D; X 11 is S; X 12 is N; X 13 is Y; X 14 is S; X 15 is S; X 16 is S; and X 17 is T.

8. The method of claim 6 , wherein the light chain variable region comprises light chain framework sequences LC-FR1, LC-FR2, LC-FR3 and LC-FR4, interposed between the HVRs, thus forming a sequence of the formula: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4).

9. The method of claim 8 , wherein one or more of the light chain framework sequences is selected from:

(a)

(SEQ ID NO: 11)

LC-FR1 is QSALTQPASVSGSPGQSITISC;

(b)

(SEQ ID NO: 12)

LC-FR2 is WYQQHPGKAPKLMIY;

(c)

(SEQ ID NO: 13)

LC-FR3 is GVSNRFSGSKSGNTASLTISGLQAEDEADYYC;

or

(d)

(SEQ ID NO: 14)

LC-FR4 is FGTGTKVTVL.

10. The method of claim 6 , wherein the anti-PD-L1 antibody or antigen binding fragment thereof further comprises a human or murine constant region.

11. The method of claim 6 , wherein the antibody binds to human, mouse, or cynomolgus monkey PD-L1, or wherein the antibody is capable of blocking the interaction between human, mouse, or cynomolgus monkey PD-L1 and the respective human, mouse, or cynomolgus monkey PD-1 receptors.

12. The method of claim 1 , wherein:

(a) the heavy chain variable region comprises the sequence:

(SEQ ID NO: 24)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSS

IYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIK

LGTVTTVDYWGQGTLVTVSS;

and

(b) the light chain variable region comprises the sequence:

(SEQ ID NO: 25)

QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMI

YDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRV

FGTGTKVTVL.

13. The method of claim 1 , wherein the anti-PD-L1 antibody comprises:

(a) a heavy chain variable region (VH) comprising an HVR-H1, HVR-H2 and HVR-H3 of SEQ ID NO: 32; and

(b) a light chain variable region (VL) comprising an HVR-L1, HVR-L2 and HVR-L3 of SEQ ID NO: 33.

14. The method of claim 13 , wherein the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 15, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 16, the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 17, the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 18, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 19, and the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 20.

15. The method of claim 13 , wherein the anti-PD-L1 antibody comprises:

(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 32, or the amino acid sequence of SEQ ID NO: 32 without the C-terminal lysine; and

(b) a light chain comprising the amino acid sequence of SEQ ID NO: 33.

16. The method of claim 13 , wherein each HVR is defined in accordance with the Kabat definition, the Chothia definition, a combination of the Kabat definition and the Chothia definition, the AbM definition, or the contact definition of HVR.

17. The method of claim 1 , wherein the cancer is 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.

18. The method of claim 1 , further comprising the administration of at least one further therapeutic agent or vaccine.

19. The method of claim 18 , wherein the further therapeutic agent is cyclophosphamide and the vaccine is Tecemotide.

20. The method of claim 18 , wherein the further therapeutic agent is a chemotherapeutic agent.

21. The method of claim 20 , wherein the chemotherapeutic agent is gemcitabine.

22. The method of claim 20 , wherein the chemotherapeutic agent is cyclophosphamide.

23. The method of claim 20 , wherein the chemotherapeutic agents are 5-fluorouracil and oxaliplatin.

24. The method of claim 1 , wherein the method further comprises the application of a treatment regimen selected from the group consisting of: surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, angiogenesis inhibition and palliative care.

25. The method of claim 24 , wherein the treatment regime is radiation therapy.