ANTI-PD-L1 ANTIBODIES
Aspects of the invention include isolated anti-PD-L1 antibodies, as well as compositions containing such antibodies, and methods of using the same in the treatment of diseases or conditions that are mediated by PD-L1 signaling.
1 . A polynucleotide encoding a heavy chain or a light chain of an anti-PD-L1 antibody or antigen-binding fragment thereof, wherein the heavy chain comprises a heavy chain variable region (VH) having at least 90% sequence identity to SEQ ID NO:37 or SEQ ID NO:45, wherein the light chain comprises a light chain variable region (VL) having at least 90% sequence identity to SEQ ID NO:46, and wherein the antibody or antigen-binding fragment thereof comprises:
(i) an HVR-L1 comprising the sequence of RASQDISIWLS (SEQ ID NO:1);
(ii) an HVR-L2 comprising the sequence of KASNLHT (SEQ ID NO:2);
(iii) an HVR-L3 comprising the sequence of LQSQSFPRT (SEQ ID NO:3);
(iv) an HVR-H1 comprising the sequence of GFSLTSYDIS (SEQ ID NO:4);
(v) an HVR-H2 comprising the sequence of VIWTGVGTN (SEQ ID NO:5); and
(vi) an HVR-H3 comprising the sequence of DPYYYGMDY (SEQ ID NO:6).
2 . The polynucleotide of claim 1 , wherein the VH comprises the amino acid sequence SEQ ID NO45.
3 . The polynucleotide of claim 2 , wherein the VL comprises the amino acid sequence SEQ ID NO46.
4 . The polynucleotide of claim 1 , wherein the VH comprises the amino acid sequence SEQ ID NO:37.
5 . The polynucleotide of claim 4 , wherein the VL comprises the amino acid sequence SEQ ID NO44.
6 . The polynucleotide of claim 1 , wherein the antibody is an IgA isotype.
7 . The polynucleotide of claim 1 , wherein the antibody is an IgG isotype.
8 . The polynucleotide of claim 1 , wherein the antibody is an IgM isotype.
9 . A vector comprising a promoter operably linked to the polynucleotide of claim 1 , wherein the vector encodes the heavy chain and the light chain.
10 . A host cell comprising a first polynucleotide encoding a heavy chain of an anti-PD-L1 antibody and a second polynucleotide encoding a light chain of the anti-PD-L1 antibody, wherein the coding sequences are operably linked to a promoter, wherein the VL comprises three complementarity determining regions (CDRs), such that
(i) VL CDR1 comprises the sequence of SEQ ID NO: 1;
(ii) VL CDR2 comprises the sequence of SEQ ID NO:2; and
(iii) VL CDR3 comprise the sequence of SEQ ID NO:3;
and wherein the VH comprises three CDRs, such that
(iv) VH CDR1 comprises the sequence of SEQ ID NO:4;
(v) VH CDR2 comprises the sequence of SEQ ID NO:5, and
(vi) VH CDR3 comprises the sequence of SEQ ID NO:6.
11 . A method of producing an anti-PD-L1 antibody, or an antigen-binding fragment thereof, comprising: (a) culturing the host cell of claim 10 ; and (b) isolating the anti-PD-L1 antibody or the antigen-binding fragment thereof from the culture.
12 . The method of claim 11 , wherein the first polynucleotide encodes a VH having at least 90% sequence identity to SEQ ID NO: 45 and the second polynucleotide encodes a VL having at least 90% sequence identity to SEQ ID NO: 46.
13 . The method of claim 12 , wherein the VH comprises the amino acid sequence SEQ ID NO: 45 and the VL comprises the amino acid sequence SEQ ID NO: 46.
14 . The method of claim 11 , wherein the anti-PD-L1 antibody thereof is a chimeric antibody or a humanized antibody.
15 . The method of claim 11 , wherein: the first polynucleotide encodes a VH having at least 90% sequence identity to the sequence of any one of SEQ ID NOS: 36, 37, 38, 39, 40, 41, or 42; and wherein the second polynucleotide encodes a VL having at least 90% sequence identity to any one of SEQ ID NOS: 43 or 44.
16 . The method of claim 15 , wherein the first polynucleotide encodes SEQ ID NO: 36, 37, 38, 39, 40, 41, or 42 and the second polynucleotide encodes SEQ ID NO: 43 or 44.
17 . The method of claim 11 , wherein the anti-PD-L1 antibody or the antigen-binding fragment thereof is bispecific.
18 . The method of claim 17 , wherein the bispecific antibody or antigen-binding fragment binds to a PD-L1 protein and a cell surface protein.
19 . The method of claim 18 , wherein the cell surface protein is selected from the group consisting of: CD20, EGFR, HER2, CTLA-4, TIM3, LAG3, VISTA and TIGIT.
20 . The method of claim 11 , wherein the antigen-binding fragment is selected from the group consisting of: Fab, Fab′, F(ab) 2 , F(ab′) 2 , Fv, and scFv.
21 . The method of claim 11 , wherein the antibody is an IgG, IgM, IgA, IgD, or IgE isotype.
22 . The method of claim 21 , wherein the antibody is an IgM isotype.
23 . The method of claim 22 , wherein the antibody comprises a J-chain.
24 . The method of claim 21 , wherein the antibody is an IgA isotype, wherein the antibody is a subclass selected from the group consisting of: IgA1 and IgA2, and wherein the antibody comprises a J-chain.
25 . The method of claim 23 , wherein the J-chain is a modified J-chain comprising an extraneous binding moiety.
26 . The method of claim 11 , wherein the anti-PD-L1 antibody or the antigen-binding fragment thereof is a PD-L1 antagonist.
27 . The method of claim 16 , wherein the VH comprises the amino acid sequence SEQ ID NO: 37 and the VL comprises the amino acid sequence SEQ ID NO: 44.
28 . The method of claim 11 , further comprising: (c) transfecting the host cell with a composition comprising the first and the second polynucleotides.
29 . The method of claim 28 , where the composition further comprises a third polynucleotide encoding a J-chain.
30 . The method of claim 29 , wherein the J-chain is a modified J-chain comprising an extraneous binding moiety.