Anti-PD-L1 antibodies and uses thereof
The present application relates to anti-PD-L1 antibodies or antigen binding fragments thereof, nucleic acid encoding the same, therapeutic compositions thereof, and their use to enhance T-cell function to upregulate cell-mediated immune responses and for the treatment of T cell dysfunctional disorders, such as tumor immunity, for the treatment of and cancer.
1. An isolated anti-PD-L1 antibody or antigen binding fragment thereof which binds to a functional epitope comprising residues Y56 and D61 of human PD-L1 (SEQ ID NO:28), wherein the anti-PD-L1 antibody or antigen binding fragment thereof comprises:
(a) a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3 sequences, wherein:
(SEQ ID NO: 8)
(i) the HVR-L1 sequence is TGTX 7 X 8 DVGX 9 YNYVS
and
(SEQ ID NO: 10)
(ii) the HVR-L3 sequence is SSX 13 TX 14 X 15 X 16 X 17 RV;
and
wherein:
X 7 is N or S,
X 8 is T, R or S,
X 9 is A or G,
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, and
(b) a heavy chain variable region.
2. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 1 wherein the functional epitope further comprises residues E58, E60, Q66, R113 and M115 of human PD-L1 (SEQ ID NO:28).
3. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 2 , wherein the isolated anti-PD-L1 antibody or antigen binding fragment further binds to a conformational epitope comprising residues 54-66 and 112-122 of human PD-L1 (SEQ ID NO:28).
4. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 1 , wherein the constant region of the anti-PD-L1 antibody is IgG1.
5. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 1 , 2 , or 3 , wherein the:
heavy chain variable region comprises HVR-H1, HVR-H2, and HVR-H3 sequences, wherein:
(SEQ ID NO: 1)
(a) the HVR-H1 sequence is X 1 YX 2 MX 3 ;
(SEQ ID NO: 2)
(b) the HVR-H2 sequence is SIYPSGGX 4 TFYADX 5 VKG;
and
(SEQ ID NO: 3)
(c) 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.
6. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 5 , 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.
7. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 5 , 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).
8. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 7 , wherein one or more of the heavy chain framework sequences is selected from:
(SEQ ID NO: 4)
(a) HC-FR1 is EVQLLESGGGLVQPGGSLRLSCAASGFTFS;
(SEQ ID NO: 5)
(b) HC-FR2 is WVRQAPGKGLEWVS;
(SEQ ID NO: 6)
(c) HC-FR3 is RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR;
or
(SEQ ID NO: 7)
(d) HC-FR4 is WGQGTLVTVSS.
9. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 5 , wherein:
(a) X 7 is N or S; X 8 is T, R or S; X 9 is A or G; 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 13 is Y; X 14 is S; X 15 is S; X 16 is S; and X 17 is T.
10. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 5 , 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).
11. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 5 , wherein one or more of the light chain framework sequences is selected from:
(SEQ ID NO: 11)
(a) LC-FR1 is QSALTQPASVSGSPGQSITISC;
(SEQ ID NO: 12)
(b) LC-FR2 is WYQQHPGKAPKLMIY;
(SEQ ID NO: 13)
(c) LC-FR3 is GVSNRFSGSKSGNTASLTISGLQAEDEADYYC;
or
(SEQ ID NO: 14)
(d) LC-FR4 is FGTGTKVTVL.
12. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 5 , wherein the anti-PD-L1 antibody or antigen binding fragment thereof further comprises a human or murine constant region.
13. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 5 , 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.
14. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 5 , 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.
15. The isolated anti-PD-L1 antibody or antigen binding fragment 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.
16. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 1 , 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, and the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 20.
17. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 15 , 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.
18. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 15 , 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.
19. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 1 , wherein:
(a) X 7 is N or S; X 8 is T, R or S; X 9 is A or G; X 12 is N; 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 13 is Y; X 14 is S; X 15 is S; X 16 is S; and X 17 is T.
20. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 1 , 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).
21. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 20 , wherein one or more of the light chain framework sequences is selected from:
(SEQ ID NO: 11)
(e) LC-FR1 is QSALTQPASVSGSPGQSITISC;
(SEQ ID NO: 12)
(f) LC-FR2 is WYQQHPGKAPKLMIY;
(SEQ ID NO: 13)
(g) LC-FR3 is GVSNRFSGSKSGNTASLTISGLQAEDEADYYC;
or
(SEQ ID NO: 14)
(h) LC-FR4 is FGTGTKVTVL.