Anti-PD-L1 and IL-2 cytokines
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. An immunocytokine comprising
an IL-2 cytokine linked to a C-terminal end of a light chain of an immunoglobulin,
wherein the light chain of the immunoglobulin comprises in N- to C-terminal direction:
a) a V L domain comprising CDRL1, CDRL2 and CDRL3;
b) a light chain constant region, (C L ); and
wherein the V L domain comprises
i) the CDRL1 sequence of SEQ ID NO: 37 or 40; and
ii) the CDRL2 sequence of SEQ ID NO: 38 or 41 or the CDRL2 sequence of light chain sequence SEQ ID NO: 50; and
iii) the CDRL3 sequence of SEQ ID NO: 39 or 42; and
wherein the immunocytokine further comprises a heavy chain that comprises in N- to C-terminal direction:
a) a V H domain comprising CDRH1, CDRH2 and CDRH3; and
b) a heavy chain constant region (C H ); and
wherein the V H domain comprises
i) the CDRH1 sequence of SEQ ID NO: 27 or 30; and
ii) the CDRH2 sequence of SEQ ID NO: 28 or 31; and
iii) the CDRH3 sequence of SEQ ID NO: 29 or 32 and
the immunocytokine optionally further comprises a linker, (L) that links the IL-2 cytokine to the C-terminal end of the light chain; wherein the V H domain and V L domain are comprised by an antigen-binding site that specifically binds to hPD-L1 as defined by SEQ ID NO: 1 and that inhibits binding of PD-L1 to PD-1.
2. The immunocytokine of claim 1 , wherein the V H domain is derived from the recombination of a human IGHV3 V H gene segment, a human D gene segment, and a human IGHJ5 J H gene segment, and wherein the V L domain is derived from the recombination of a human IGκV1D V κ gene segment and a human J κ gene segment.
3. The immunocytokine of claim 2 , wherein the human V H gene segment is IGHV3-9*01, the human J H gene segment is IGHJ5*02, and the human V κ gene segment is IGKV1D-39*01.
4. The immunocytokine of claim 1 , wherein the V H domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 33.
5. The immunocytokine of claim 1 , wherein the heavy chain comprises the V H domain sequence of heavy chain sequence SEQ ID NO: 47, SEQ ID NO: 48, or SEQ ID NO: 49.
6. The immunocytokine of claim 1 , wherein the V L domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 43.
7. The immunocytokine of claim 1 , wherein the immunocytokine further comprises a human constant region.
8. The immunocytokine of claim 7 , wherein the human constant region is an IgG1 constant region.
9. The immunocytokine of claim 1 , wherein the V H domain comprises the amino acid sequence of SEQ ID NO: 33 and the V L domain comprises the amino acid sequence of SEQ ID NO: 43.
10. The immunocytokine of claim 1 , wherein the IL-2 cytokine is human IL-2 (hIL-2) or a variant thereof.
11. The immunocytokine of claim 10 , wherein the hIL-2 comprises or consists of the amino acid sequence of SEQ ID NO: 301 or a variant thereof comprising a modification at the N-terminus of SEQ ID NO: 301.
12. A pharmaceutical composition comprising the immunocytokine of claim 1 and a pharmaceutically acceptable excipient, diluent, or carrier.
13. A kit comprising the pharmaceutical composition of claim 12 and a label or instructions comprising a marketing authorization number.
14. The immunocytokine of claim 1 , wherein the V H domain comprises the amino acid sequence of SEQ ID NO: 33.
15. The immunocytokine of claim 1 , wherein the VL domain comprises the amino acid sequence of SEQ ID NO: 43.
16. The immunocytokine of claim 1 , 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 95% identical to SEQ ID NO: 43.
17. The immunocytokine of claim 1 , wherein the heavy chain comprises the amino acid sequence of the V H domain of SEQ ID NO: 47 and the V L domain comprises the amino acid sequence of SEQ ID NO: 43.
18. The immunocytokine of claim 1 , wherein the heavy chain comprises the amino acid sequence of the V H domain of SEQ ID NO: 48 and the V L domain comprises the amino acid sequence of SEQ ID NO: 43.
19. The immunocytokine of claim 1 , wherein the heavy chain comprises the amino acid sequence of the V H domain of SEQ ID NO: 49 and the V L domain comprises the amino acid sequence of SEQ ID NO: 43.