Anti-pd-l1 and il-2 cytokines
AssigneeKymab Limited
InventorsJamie CAMPBELL, Nikole SANDY, Cassandra VAN KRINKS, Stephen John ARKINSTALL, Volker GERMASCHEWSKI, IAN KIRBY, Miha KOSMAC, Thomas GALLAGHER, Cecilia DEANTONIO, Stphen Douglas GILLIES
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Abstract
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.
Claims64
An immunocytokine comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the heavy chain comprises in N- to C-terminal direction:
- a) A VH domain comprising CDRH1, CDRH2 and CDRH3;
- and
- b) A heavy chain constant region;
- and wherein the light chain comprises in N- to C-terminal direction:
- c) A VL domain comprising CDRL1, CDRL2 and CDRL3;
- d) A light chain constant region, (CL);
- e) Optionally, a linker, (L);
- and
- f) An IL-2 cytokine;
- wherein the VH domain and VL domain are comprised by an antigen-binding site that specifically binds to hPD-L1 as defined by Seq ID No:1, and competes for binding to said hPD-L1 with the antibody 1D05;
- and
- wherein the immunocytokine comprises a VH domain which comprises a CDRH3 comprising the motif X1GSGX2YGX3X4FD, wherein X1, X2 and X3 are independently any amino acid, and X4 is either present or absent, and if present, may be any amino acid.
An immunocytokine comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the heavy chain comprises in N- to C-terminal direction:
- a) A VH domain comprising CDRH1, CDRH2 and CDRH3;
- and
- b) A heavy chain constant region;
- and wherein the light chain comprises in N- to C-terminal direction:
- c) A VL domain comprising CDRL1, CDRL2 and CDRL3;
- d) A light chain constant region, (CL);
- e) Optionally, a linker, (L);
- and
- f) An IL-2 cytokine;
- wherein the VH domain and VL domain are comprised by an antigen-binding site that specifically binds to hPD-L1;
- and
- wherein the VH domain comprises a CDRH3 of from 12 to 20 amino acids and which is derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, wherein the human JH gene segment is IGHJ5 (e.g. IGHJ5*02).
An immunocytokine comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the heavy chain comprises in N- to C-terminal direction:
- a) A VH domain comprising CDRH1, CDRH2 and CDRH3;
- and
- b) A heavy chain constant region;
- and wherein the light chain comprises in N- to C-terminal direction:
- c) A VL domain comprising CDRL1, CDRL2 and CDRL3;
- d) A light chain constant region, (CL);
- e) Optionally, a linker, (L);
- and
- f) An IL-2 cytokine;
- wherein the VH domain and VL domain are comprised by an antigen-binding site that specifically binds to an epitope that is identical to an epitope to which the antibody 1D05 specifically binds.
An immunocytokine comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the heavy chain comprises in N- to C-terminal direction:
- a) A VH domain comprising CDRH1, CDRH2 and CDRH3;
- and
- b) A heavy chain constant region;
- and wherein the light chain comprises in N- to C-terminal direction:
- c) A VL domain comprising CDRL1, CDRL2 and CDRL3;
- d) A light chain constant region, (CL);
- e) Optionally, a linker, (L);
- and
- f) An IL-2 cytokine;
- wherein the VH domain and VL domain are comprised by an antigen-binding site which competes for binding to hPD-L1 with the antibody 1D05.
An immunocytokine according to any preceding claim, wherein the VH domain comprises the CDRH1 sequence of SEQ ID NO:27 or 30 or the CDRH1 sequence of SEQ ID NO:27 or 30 comprising 3, 2 or 1 amino acid substitution(s).
An immunocytokine according to any preceding claim, wherein the VH domain comprises the CDRH2 sequence of SEQ ID NO:28 or 31, or the CDRH2 sequence of SEQ ID NO:28 or 31 comprising 4 or fewer amino acid substitutions.
An immunocytokine according to any preceding claim, wherein the VH domain comprises an amino acid sequence of SEQ ID NO:33, or a heavy chain variable domain amino acid sequence that is at least 80% (e.g. at least 85%, or at least 90%) identical to SEQ ID NO:33 (for example the VH domain sequence in any of the heavy chain sequences of Seq ID Nos:47 to 49).
An immunocytokine according to any preceding claim comprising first and second copies of said heavy chain.
An immunocytokine according to any preceding claim, comprising a VL domain which comprises the CDRL1 sequence of SEQ ID NO:37 or 40, or the CRDL1 sequence of SEQ ID NO:37 or 40 comprising 3 or fewer amino acid substitutions.
An immunocytokine according to any preceding claim, comprising a VL domain which comprises the CDRL2 sequence of SEQ ID NO:38 or 41, or the CRDL2 sequence of SEQ ID NO:38 or 41 comprising 2 or 1 amino acid substitution(s), for example a CDRL2 sequence of Seq ID No:50.
An immunocytokine according to any preceding claim, comprising a VL domain which comprises the CDRL3 sequence of SEQ ID NO:39 or 42, or the CRDL3 sequence of SEQ ID NO:39 or 42 comprising 4 or fewer amino acid substitutions.
An immunocytokine according to any preceding claim, comprising a VL domain which comprises an amino acid sequence of SEQ ID NO:43, or a light chain variable domain amino acid sequence that is at least 80% (e.g. at least 85%, or at least 90%) identical to SEQ ID NO:43 (for example the VL domain sequence in the light chain sequence of Seq ID No:50 or 51).
An immunocytokine according to any preceding claim comprising first and second copies of said light chain.
An immunocytokine according to any preceding claim which specifically binds to cynomolgus PD-L1 as defined by Seq ID No:2.
An immunocytokine according to any preceding claim, wherein the antibody or fragment comprises a kappa light chain.
An immunocytokine according to any preceding claim, wherein the antibody or fragment comprises a constant region, e.g. an IgG1 constant region, optionally wherein the constant region is a disabled IgG1 as defined in Seq ID No:205.
An immunocytokine according to any preceding claim wherein the:
- A) VH domain comprises an amino acid sequence of SEQ ID No:33 and the VL domain comprises an amino acid sequence of SEQ ID No:43;
- B) VH domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:33, and the VL domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:43;
- C) VH domain comprises an amino acid sequence of the VH domain of SEQ ID No:47 and the VL domain comprises an amino acid sequence of SEQ ID No:43;
- D) VH domain comprises an amino acid sequence of the VH domain of SEQ ID No:48 and the VL domain comprises an amino acid sequence of SEQ ID No:43;
- E) VH domain comprises an amino acid sequence of the VH domain of SEQ ID No:49 and the VL domain comprises an amino acid sequence of SEQ ID No:43;
- F) VH domain comprises an amino acid sequence of the VH domain of SEQ ID No:342 and the VL domain comprises an amino acid sequence of SEQ ID No:43;
- G) VH domain comprises an amino acid sequence of SEQ ID No:33 and the VL domain comprises an amino acid sequence of the VL domain of SEQ ID No:50;
- H) VH domain comprises an amino acid sequence of the VH domain of SEQ ID No:47 and the VL domain comprises an amino acid sequence of the VL domain of SEQ ID No:50;
- I) VH domain comprises an amino acid sequence of the VH domain of SEQ ID No:48 and the VL domain comprises an amino acid sequence of the VL domain of SEQ ID No:50;
- J) VH domain comprises an amino acid sequence of the VH domain of SEQ ID No:49 and the VL domain comprises an amino acid sequence of the VL domain of SEQ ID No:50;
- K) VH domain comprises an amino acid sequence of the VH domain of SEQ ID No:342 and the VL domain comprises an amino acid sequence of the VL domain of SEQ ID No:50;
- L) VH domain comprises an amino acid sequence of SEQ ID No:33 and the VL domain comprises an amino acid sequence of the VL domain of SEQ ID No:51;
- M) VH domain comprises an amino acid sequence of the VH domain of SEQ ID No:47 and the VL domain comprises an amino acid sequence of the VL domain of SEQ ID No:51;
- N) VH domain comprises an amino acid sequence of the VH domain of SEQ ID No:48 and the VL domain comprises an amino acid sequence of the VL domain of SEQ ID No:51;
- O) VH domain comprise an amino acid sequence of the VH domain of SEQ ID No:49 and the VL domain comprises an amino acid sequence of the VL domain of SEQ ID No:51;
- P) VH domain comprise an amino acid sequence of the VH domain of SEQ ID No:342 and the VL domain comprises an amino acid sequence of the VL domain of SEQ ID No:51;
- Q) VH domain comprises an amino acid sequence of SEQ ID No:33 and the VL domain comprises an amino acid sequence of the VL domain of SEQ ID No:298;
- R) VH domain comprises an amino acid sequence of the VH domain of SEQ ID No:47 and the VL domain comprises an amino acid sequence of the VL domain of SEQ ID No:298;
- S) VH domain comprises an amino acid sequence of the VH domain of SEQ ID No:48 and the VL domain comprises an amino acid sequence of the VL domain of SEQ ID No:298;
- T) VH domain comprise an amino acid sequence of the VH domain of SEQ ID No:49 and the VL domain comprises an amino acid sequence of the VL domain of SEQ ID No:298;
- U) VH domain comprise an amino acid sequence of the VH domain of SEQ ID No:342 and the VL domain comprises an amino acid sequence of the VL domain of SEQ ID No:298;
- V) VH domain comprises an amino acid sequence of SEQ ID No:58 and the VL domain comprises an amino acid sequence of SEQ ID No:68;
- W) VH domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:58, and the VL domain comprise an amino acid sequence that is at least 85% identical to SEQ ID No:68;
- X) VH domain comprises an amino acid sequence of SEQ ID No:78 and the VL domain comprises an amino acid sequence of SEQ ID No:88;
- Y) VH domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:78, and the VL domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:88;
- Z) VH domain comprises an amino acid sequence of SEQ ID No:98 and the VL domain comprises an amino acid sequence of SEQ ID No:108;
- AA) VH domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:98, and the VL domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:108;
- BB) VH domain comprises an amino acid sequence of SEQ ID No:118 and the VL domain comprises an amino acid sequence of SEQ ID No:128;
- CC) VH domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:118, and the VL domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:128;
- DD) VH domain comprises an amino acid sequence of SEQ ID No:158 and the VL domain comprises an amino acid sequence of SEQ ID No:168;
- EE) VH domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:158, and the VL domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:168;
- FF) VH domain comprises an amino acid sequence of SEQ ID No:178 and the VL domain comprises an amino acid sequence of SEQ ID No:188;
- GG) VH domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:178, and the VL domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:188;
- HH) VH domain comprises an amino acid sequence of SEQ ID No:138 and the VL domain comprises an amino acid sequence of SEQ ID No:148;
- II) VH domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:13, and the VL domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:148;
- JJ) VH domain comprises an amino acid sequence of SEQ ID No:244 and the VL domain comprises an amino acid sequence of SEQ ID No:254;
- KK) VH domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:244, and the VL domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:254;
- LL) VH domain comprises an amino acid sequence of SEQ ID No:264 and the VL domain comprises an amino acid sequence of SEQ ID No:274;
- MM) VH domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:264, and the VL domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:274;
- NN) VH domain comprises an amino acid sequence of SEQ ID No:284 and the VL domain comprises an amino acid sequence of SEQ ID No:294;
- OO) VH domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:284, and the VL domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:294;
- PP) VH domain comprises an amino acid sequence of SEQ ID No:13 and the VL domain comprises an amino acid sequence of SEQ ID No:23;
- and
- QQ) VH domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:13, and the VL domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:23;
- RR) VH domain comprises an amino acid sequence of SEQ ID No:349 and the VL domain comprises an amino acid sequence of SEQ ID No:359;
- and
- SS) VH domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:349, and the VL domain comprises an amino acid sequence that is at least 85% identical to SEQ ID No:359.
An immunocytokine according to any preceding claim wherein the:
- A) VH and the constant region comprise an amino acid sequence of SEQ ID No:299 and VL and CL comprise an amino acid sequence of SEQ ID No:45;
- B) VH and the constant region comprise an amino acid sequence that is at least 85% identical to SEQ ID No:299, and the VL and CL comprise an amino acid sequence that is at least 85% identical to SEQ ID No:45;
- C) VH and the constant region comprise an amino acid sequence of SEQ ID No:47 and VL and CL comprise an amino acid sequence of SEQ ID No:45;
- D) VH and the constant region comprise an amino acid sequence of SEQ ID No:48 and VL and CL comprise an amino acid sequence of SEQ ID No:45;
- E) VH and the constant region comprise an amino acid sequence of SEQ ID No:49 and VL and CL comprise an amino acid sequence of SEQ ID No:45;
- F) VH and the constant region comprise an amino acid sequence of SEQ ID No:342 and VL and CL comprise an amino acid sequence of SEQ ID No:45;
- G) VH and the constant region comprise an amino acid sequence of SEQ ID No:238 and VL and CL comprise an amino acid sequence of SEQ ID No:50;
- H) VH and the constant region comprise an amino acid sequence of SEQ ID No:47 and VL and CL comprise an amino acid sequence of SEQ ID No:50;
- I) VH and the constant region comprise an amino acid sequence of SEQ ID No:48 and VL and CL comprise an amino acid sequence of SEQ ID No:50;
- J) VH and the constant region comprise an amino acid sequence of SEQ ID No:49 and VL and CL comprise an amino acid sequence of SEQ ID No:50;
- K) VH and the constant region comprise an amino acid sequence of SEQ ID No:342 and VL and CL comprise an amino acid sequence of SEQ ID No:50;
- L) VH and the constant region comprise an amino acid sequence of SEQ ID No:299 and VL and CL comprise an amino acid sequence of SEQ ID No:51;
- M) VH and the constant region comprise an amino acid sequence of SEQ ID No:47 and VL and CL comprise an amino acid sequence of SEQ ID No:51;
- N) VH and the constant region comprise an amino acid sequence of SEQ ID No:48 and VL and CL comprise an amino acid sequence of SEQ ID No:51;
- O) VH and the constant region comprise an amino acid sequence of SEQ ID No:49 and VL and CL comprise an amino acid sequence of SEQ ID No:51;
- P) VH and the constant region comprise an amino acid sequence of SEQ ID No:342 and VL and CL comprise an amino acid sequence of SEQ ID No:51;
- Q) VH and the constant region comprise an amino acid sequence of SEQ ID No:299 and VL and CL comprise an amino acid sequence of SEQ ID No:298;
- R) VH and the constant region comprise an amino acid sequence of SEQ ID No:47 and VL and CL comprise an amino acid sequence of SEQ ID No:298;
- S) VH and the constant region comprise an amino acid sequence of SEQ ID No:48 and VL and CL comprise an amino acid sequence of SEQ ID No:298;
- T) VH and the constant region comprise an amino acid sequence of SEQ ID No:49 and VL and CL comprise an amino acid sequence of SEQ ID No:298;
- U) VH and the constant region comprise an amino acid sequence of SEQ ID No:342 and VL and CL comprise an amino acid sequence of SEQ ID No:298;
- V) VH and the constant region comprise an amino acid sequence of SEQ ID No:60 and VL and CL comprise an amino acid sequence of SEQ ID No:70;
- W) VH and the constant region comprise an amino acid sequence that is at least 85% identical to SEQ ID No:60, and the VL and CL comprise an amino acid sequence that is at least 85% identical to SEQ ID No:70;
- X) VH and the constant region comprise an amino acid sequence of SEQ ID No:80 and VL and CL comprise an amino acid sequence of SEQ ID No:90;
- Y) VH and the constant region comprise an amino acid sequence that is at least 85% identical to SEQ ID No:80, and the VL and CL comprise an amino acid sequence that is at least 85% identical to SEQ ID No:90;
- Z) VH and the constant region comprise an amino acid sequence of SEQ ID No:100 and VL and CL comprise an amino acid sequence of SEQ ID No:110;
- AA) VH and the constant region comprise an amino acid sequence that is at least 85% identical to SEQ ID No:100, and the VL and CL comprise an amino acid sequence that is at least 85% identical to SEQ ID No:110;
- BB) VH and the constant region comprise an amino acid sequence of SEQ ID No:120 and VL and CL comprise an amino acid sequence of SEQ ID No:130;
- CC) VH and the constant region comprise an amino acid sequence that is at least 85% identical to SEQ ID No:120, and the VL and CL comprise an amino acid sequence that is at least 85% identical to SEQ ID No:130;
- DD) VH and the constant region comprise an amino acid sequence of SEQ ID No:160 and VL and CL comprise an amino acid sequence of SEQ ID No:170;
- EE) VH and the constant region comprise an amino acid sequence that is at least 85% identical to SEQ ID No:160, and the VL and CL comprise an amino acid sequence that is at least 85% identical to SEQ ID No:170;
- FF) VH and the constant region comprise an amino acid sequence of SEQ ID No:180 and VL and CL comprise an amino acid sequence of SEQ ID No:190;
- GG) VH and the constant region comprise an amino acid sequence that is at least 85% identical to SEQ ID No:180, and the VL and CL comprise an amino acid sequence that is at least 85% identical to SEQ ID No:190;
- HH) VH and the constant region comprise an amino acid sequence of SEQ ID No:140 and VL and CL comprise an amino acid sequence of SEQ ID No:150;
- II) VH and the constant region comprise an amino acid sequence that is at least 85% identical to SEQ ID No:140, and the VL and CL comprise an amino acid sequence that is at least 85% identical to SEQ ID No:150;
- JJ) VH and the constant region comprise an amino acid sequence of SEQ ID No:246 and VL and CL comprise an amino acid sequence of SEQ ID No:256;
- KK) VH and the constant region comprise an amino acid sequence that is at least 85% identical to SEQ ID No:246, and the VL and CL comprise an amino acid sequence that is at least 85% identical to SEQ ID No:256;
- LL) VH and the constant region comprise an amino acid sequence of SEQ ID No:266 and VL and CL comprise an amino acid sequence of SEQ ID No:276;
- MM) VH and the constant region comprise an amino acid sequence that is at least 85% identical to SEQ ID No:266, and the VL and CL comprise an amino acid sequence that is at least 85% identical to SEQ ID No:276;
- NN) VH and the constant region comprise an amino acid sequence of SEQ ID No:286 and VL and CL comprise an amino acid sequence of SEQ ID No:296;
- and
- OO) VH and the constant region comprise an amino acid sequence that is at least 85% identical to SEQ ID No:286, and the VL and CL comprise an amino acid sequence that is at least 85% identical to SEQ ID No:296;
- PP) VH and the constant region comprise an amino acid sequence of SEQ ID No:15 and VL and CL comprise an amino acid sequence of SEQ ID No:25;
- and
- QQ) VH and the constant region comprise an amino acid sequence that is at least 85% identical to SEQ ID No:15, and the VL and CL comprise an amino acid sequence that is at least 85% identical to SEQ ID No:25.
- RR) VH and the constant region comprise an amino acid sequence of SEQ ID No:351 and VL and CL comprise an amino acid sequence of SEQ ID No:361;
- and
- SS) VH and the constant region comprise an amino acid sequence that is at least 85% identical to SEQ ID No:351, and the VL and CL comprise an amino acid sequence that is at least 85% identical to SEQ ID No:361.
An immunocytokine according to any preceding claim wherein the antigen-binding site specifically binds PD-L1, whilst the IL-2 cytokine binds the high affinity (αβγ) IL-2 receptor (IL-2R).
An immunocytokine according to any preceding claim wherein the immunocytokine is capable of inhibiting PD-L1-mediated suppression of T-cells.
An immunocytokine according to any preceding claim wherein the immunocytokine is capable of increasing IL-2R-mediated T-cell activation.
An immunocytokine according to any preceding claim which does not comprise a linker (L), or an immunocytokine according to any preceding claim wherein the CL of d) is directly fused to the cytokine of f).
An immunocytokine according to any preceding claim wherein the IL-2 cytokine is human IL-2 (hIL-2) or a variant thereof.
An immunocytokine according to any preceding claim, wherein the IL-2 cytokine binds to the high affinity (αβγ) IL-2 receptor with a potency less than free IL-2, for example with an ECK of greater than 20 pM, greater than 50 pM or greater than 100 pM, e.g. when measured in a cell-based proliferative assay.
An immunocytokine according to any preceding claim, wherein the IL-2 binds to the intermediate affinity (βγ) IL-2 receptor with a potency less than free IL-2, for example with an EC50 of greater than 1 nM, greater than 5 nM or greater than 10 nM, e.g. when measured in a cell-based proliferative assay.
An immunocytokine according to any preceding claim, wherein the IL-2 preferentially binds to the high affinity (αβγ) IL-2 receptor over the intermediate affinity (βγ) IL-2 receptor.
An immunocytokine according to any preceding claim, wherein the antigen binding site binds to hPD-L1 with an affinity of less than 500 pM (e.g. less than 300 pM or less than 200 pM), optionally wherein the immunocytokine provides a ratio of the potency of the IL-2 cytokine against the high affinity (αβγ) receptor:
- affinity of the anti-PD-L1 antigen binding site against hPD-L1 of at least 2:1.
An immunocytokine as defined in any preceding claim for use in treating or preventing a hPD-L1-mediated disease or condition, e.g. selected from neoplastic or non-neoplastic disease, chronic viral infections, and malignant tumours, such as melanoma, breast cancer, ovarian cancer, Merkel cell carcinoma, non-small cell lung cancer (squamous and non-squamous), renal cell cancer, bladder cancer, colorectal cancer (without MSI or microsatellite instability), head and neck squamous cell carcinoma, mesothelioma, virally induced cancers (such as cervical cancer and nasopharyngeal cancer), soft tissue sarcomas, haematological malignancies such as Hodgkin's and non-Hodgkin's disease, diffuse large B-cell lymphoma (for example melanoma, breast cancer, ovarian cancer, Merkel cell carcinoma, non-small cell lung cancer (squamous and non-squamous), renal cell cancer, bladder cancer, colorectal cancer (without MSI or microsatellite instability), head and neck squamous cell carcinoma and mesothelioma or for example virally induced cancers (such as cervical cancer and nasopharyngeal cancer) and soft tissue sarcomas).
An antibody or a fragment thereof, which specifically binds to hPD-L1 as defined by Seq ID No:1, and competes for binding to said hPD-L1 with the antibody 1D05, wherein the antibody or fragment comprises a VH domain which comprises a CDRH3 comprising the motif X1GSGX2YGX3X4FD, wherein X1, X2 and X3 are independently any amino acid, and X4 is either present or absent, and if present, may be any amino acid.
Dependencies are inferred from the claim text.