Anti-PD-L1 antibodies and uses thereof

Patent metadata

Field	Value
Publication number	US-9624298-B2
Application number	US-201214360775-A
Country	US
Kind code	B2
Filing date	Nov 21, 2012
Priority date	Nov 28, 2011
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

Abstract

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.

First claim

The invention claimed is:

1. An isolated anti-PD-L1 antibody or antigen binding fragment thereof comprising:
a light chain variable region; and
a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3 sequences, wherein:
(a) the HVR-H1 sequence is X 1 YX 2 MX 3 (SEQ ID NO:1);
(b) the HVR-H2 sequence is SIYPSGGX 4 TFYADX 5 VKG (SEQ ID NO:2); and
(c) the HVR-H3 sequence is IKLGTVTTVX 6 Y (SEQ ID NO:3);
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 isolated anti-PD-L1 antibody or antigen binding fragment 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.

3. The isolated anti-PD-L1 antibody or antigen binding fragment 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).

4. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 3 , wherein the heavy chain framework sequences are derived from human consensus heavy chain framework sequences or from human germline heavy chain framework sequences.

5. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 3 , wherein one or more of the heavy chain framework sequences is selected from:

(a) HC-FR1 is

(SEQ ID NO: 4)

EVQLLESGGGLVQPGGSLRLSCAASGFTFS;

(b) HC-FR2 is 

(SEQ ID NO: 5)

WVRQAPGKGLEWVS;

(c) HC-FR3 is 

(SEQ ID NO: 6)

RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR; or

(d) HC-FR4 is

(SEQ ID NO: 7)

WGQGTLVTVSS.

6. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 5 , further comprising a C H 1 domain or a C H 1, a C H 2 and a C H 3 domain.

7. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 1 , wherein the light chain variable region comprises HVR-L1, HVR-L2 and HVR-L3 sequences, wherein:
(a) the HVR-L1 sequence is TGTX 7 X 8 DVGX 9 YNYVS (SEQ ID NO: 8);
(b) the HVR-L2 sequence is X 10 VX 11 X 12 RPS (SEQ ID NO: 9); and
(c) the HVR-L3 sequence is SSX 13 TX 14 X 15 X 16 X 17 RV (SEQ ID NO: 10);
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.

8. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 7 , 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 II 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.

9. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 7 , 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).

10. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 9 , wherein the light chain framework sequences are derived from human consensus light chain framework sequences or human germline light chain framework sequences.

11. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 9 , wherein one or more of the light chain framework sequences is selected from:

(a) LC-FR1 is

(SEQ ID NO: 11)

QSALTQPASVSGSPGQSITISC;

(b) LC-FR2 is

(SEQ ID NO: 12)

WYQQHPGKAPKLMIY;

(c) LC-FR3 is

(SEQ ID NO: 13)

GVSNRFSGSKSGNTASLTISGLQAEDEADYYC; or

(d) LC-FR4 is

(SEQ ID NO: 14)

FGTGTKVTVL.

12. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 11 , further comprising a C L domain.

13. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 7 further comprising a human or murine constant region.

14. The isolated anti-PD-L1 antibody or antigen binding fragment of claim 13 , wherein the constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.

15. An isolated anti-PD-L1 antibody or antigen binding fragment thereof comprising a heavy chain variable region and a light chain variable region, wherein:
(a) the heavy chain variable region comprises an HVR-H1, an HVR-H2, and an HVR-H3, having at least 80% overall sequence identity to SYIMM (SEQ ID NO: 15), SIYPSGGITFYADTVKG (SEQ ID NO: 16), and IKLGTVTTVDY (SEQ ID NO: 17), respectively; and
(b) the light chain variable region comprises an HVR-L1, an HVR-L2, and an HVR-L3, having at least 80% overall sequence identity to TGTSSDVGGYNYVS (SEQ ID NO: 18), DVSNRPS (SE

Assignees

• Merck Patent Gmbh

Inventors

• Nastri Horacio G
• Iffland Christel
• Leger Olivier
• An Qi
• Cartwright Mark
• Mckenna Sean D

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title