ANTI-PD-L1 ANTIBODIES
The present invention relates to anti-PD-L1 antibodies, bispecific antibodies containing one domain with specificity to PD-L1, and to immunocytokines comprising an anti-PD-L1 antibody fused to a cytokine, such as IL-2. The present invention also provides methods of treatment, uses and pharmaceutical compositions comprising the antibodies, bispecific antibodies and immunocytokines.
1 - 61 . (canceled)
62 . An antibody or antigen binding fragment thereof that specifically binds to hPD-L1, comprising a V H domain and a V L domain, wherein the V H domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 33, and the V L domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 43.
63 . The antibody or antigen binding fragment of claim 62 , wherein the V L domain comprises the amino acid sequence of SEQ ID NO: 43 and the V H domain comprises an amino acid sequence selected from the group consisting of:
a) the V H domain of heavy chain amino acid sequence SEQ ID NO: 47;
b) the V H domain of heavy chain amino acid sequence SEQ ID NO: 48;
c) the V H domain of heavy chain amino acid sequence SEQ ID NO: 49;
d) the V H domain of heavy chain amino acid sequence SEQ ID NO: 342; and
e) SEQ ID NO: 33.
64 . The antibody or antigen binding fragment of claim 62 , wherein the wherein the V L domain comprises the amino acid sequence of SEQ ID NO: 43 and the V H domain comprises the amino acid sequence of SEQ ID NO: 33.
65 . The antibody or antigen binding fragment of claim 62 , wherein the V H domain comprises an amino acid sequence of SEQ ID NO: 33, 47, 48, or 342 and the V H domain comprises an amino acid sequence selected from the group consisting of:
a) the V L domain of light chain amino acid sequence SEQ ID NO: 50;
b) the V L domain of light chain amino acid sequence SEQ ID NO: 51; and
c) the V L domain of light chain amino acid sequence SEQ ID NO: 298.
66 . The antibody or antigen binding fragment of claim 62 , wherein the antibody or fragment comprises the CDRH3 sequence of SEQ ID NO: 29 or 32, and/or the CDRH1 sequence of SEQ ID NO: 27 or 30, and/or the CDRH2 sequence of SEQ ID NO: 28 or 31 and/or the CDRL1 sequence of SEQ ID NO: 37 or 40, and/or the CDRL2 sequence of SEQ ID NO: 38 or 41, and/or the CDRL3 sequence of SEQ ID NO: 39 or 42.
67 . The antibody or antigen binding fragment of claim 66 , wherein the antibody or fragment comprises:
a. the CDRH1 amino acid sequence of SEQ ID NO: 27 or SEQ ID NO: 30, the CDRH2 amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 31, the CDRH3 amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 32, the CDRL1 amino acid sequence of SEQ ID NO: 37 or SEQ ID NO: 40, the CDRL2 amino acid sequence of SEQ ID NO: 38 or SEQ ID NO: 41, and the CDRL3 amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 42;
b. the CDRH1 amino acid sequence of SEQ ID NO: 27 or SEQ ID NO: 30, the CDRH2 amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 31, the CDRH3 amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 32, the CDRL1 amino acid sequence of SEQ ID NO: 37 or SEQ ID NO: 40, the CDRL2 amino acid sequence as defined by the Kabat or IMGT systems from the V L sequence of SEQ ID NO: 50, and the CDRL3 amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 42; or
c. the CDRH1 amino acid sequence of SEQ ID NO: 27 or SEQ ID NO: 30, the CDRH2 amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 31, the CDRH3 amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 32, the CDRL1 amino acid sequence of SEQ ID NO: 37 or SEQ ID NO: 40, the CDRL2 amino acid sequence as defined by the Kabat or IMGT systems from the V L sequence of SEQ ID No: 298, and the CDRL3 amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 42.
68 . The antibody or antigen binding fragment of claim 62 , wherein the antibody or fragment specifically binds to cynomolgus PD-L1 as defined by SEQ ID NO: 2.
69 . The antibody or antigen binding fragment of claim 62 , wherein the antibody or fragment comprises a constant region.
70 . The antibody or antigen binding fragment of claim 69 , wherein the constant region is an effector-null human constant region, and wherein the effector-null human constant region is an IgG4 constant region or an IgG1 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO: 199) or a disabled IgG1 of SEQ ID NO: 205.
71 . A bispecific antibody or fusion protein comprising an antibody or antigen binding fragment of claim 62 .
72 . The bispecific antibody of claim 71 , wherein the bispecific format is selected from the group consisting of DVD-Ig, mAb 2 , FIT-Ig, mAb-dAb, dock and lock, SEEDbody, scDiabody-Fc, diabody-Fc, tandem scFv-Fc, Fab-scFv-Fc, Fab-scFv, intrabody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH 3 , Diabody-CH 3 , minibody, knobs-in-holes, knobs-in-holes with common light chain, knobs-in-holes with common light chain and charge pairs, charge pairs, and charge pairs with common light chain.
73 . The bispecific antibody of claim 71 , wherein the bispecific antibody specifically binds to hPD-L1 and another target antigen selected from the group consisting of an immune checkpoint inhibitor, an immune modulator, and an immune activator.
74 . A method of treating or preventing a hPD-L1 mediated disease or condition in a human, comprising administering to said human a therapeutically effective amount of the antibody or antigen binding fragment of claim 62 ,
wherein the disease or condition is selected from the group consisting of a neurodegenerative disease or condition, neoplastic disease, non-neoplastic disease, chronic viral infection, and cancer,
and wherein the hPD-L1 mediated disease or condition is thereby treated or prevented.
75 . A pharmaceutical composition comprising the antibody or antigen binding fragment of claim 62 and a pharmaceutically acceptable excipient, diluent or carrier.
76 . The pharmaceutical composition of claim 75 , further comprising a chemokine receptor antagonist selected from the group consisting of CXCR4, CCR4, and CXCR2.
77 . A method of treating or preventing a hPD-L1 mediated disease or condition in a human, comprising administering to said human a therapeutically effective amount of the pharmaceutical composition of claim 75 ,
wherein the hPD-L1-mediated condition or disease selected from the group consisting of a neurodegenerative disease or condition, neoplastic disease, non-neoplastic disease, chronic viral infection, and cancer,
and wherein the hPD-L1 mediated disease or condition is thereby treated or prevented.
78 . A nucleic acid that encodes a heavy chain or a light chain of the antibody or antigen binding fragment of claim 62 .
79 . A vector comprising the nucleic acid of claim 78 .
80 . The vector of claim 79 , wherein the vector is a CHO vector or a HEK293 vector.
81 . A host cell comprising the vector of claim 80 .