IL-18/IL-23 MULTISPECIFIC ANTIGEN BINDING PROTEINS
The present disclosure provides multispecific antigen binding proteins that bind to one or more cytokines, more particularly to pro-inflammatory cytokines. In particular, the present disclosure relates to multispecific antigen binding proteins that comprise an interleukin 18 (IL-18) binding domain and an interleukin 23 (IL-23) binding domain, and the use of said multispecific antigen binding proteins in medicine.
1 . A multispecific antigen binding protein comprising an interleukin 18 (IL-18) binding domain and an interleukin 23 (IL-23) binding domain.
2 . The multispecific antigen binding protein of claim 1 wherein said IL-18 binding domain binds to human IL-18 and said IL-23 binding domain binds to human IL-23.
3 . The multispecific antigen binding protein of claim 1 wherein said IL-23 binding domain binds to human IL-23-p19.
4 . The multispecific antigen binding protein of claim 1 wherein said multispecific antigen binding protein comprises an IL-18 binding domain comprising the following CDRs: CDRH1 of SEQ ID NO: 2, CDRH2 of SEQ ID NO: 3, CDRH3 of SEQ ID NO: 4, CDRL1 of SEQ ID NO: 5, CDRL2 of SEQ ID NO: 6 and CDRL3 of SEQ ID NO: 7 and an IL-23 binding domain comprising the following CDRs: CDRH1 of SEQ ID NO: 10, CDRH2 of SEQ ID NO: 11, CDRH3 of SEQ ID NO: 12, CDRL1 of SEQ ID NO: 13, CDRL2 of SEQ ID NO: 14 and CDRL3 of SEQ ID NO: 15.
5 . The multispecific antigen binding protein of claim 1 wherein said multispecific antigen binding protein comprises:
i. an IL-18 binding domain comprising a VH domain comprising a sequence at least 90% identical or at least 95% identical to SEQ ID NO: 8 and a VL domain comprising a sequence at least 90% identical or at least 95% identical to SEQ ID NO: 9; and
ii. an IL-23 binding domain comprising a VH domain comprising a sequence at least 90% identical or at least 95% identical to SEQ ID NO: 16 and a VL domain comprising a sequence at least 90% identical or at least 95% identical to SEQ ID NO: 17.
6 . The multispecific antigen binding protein of claim 1 wherein said multispecific antigen binding protein comprises:
i. an IL-18 binding domain comprising a VH domain of SEQ ID NO: 8 and a VL domain of SEQ ID NO: 9; and
ii. an IL-23 binding domain comprising a VH domain of SEQ ID NO: 16 and a VL domain of SEQ ID NO: 17.
7 . The multispecific antigen binding protein of claim 4 comprising an Fc domain.
8 . The multispecific antigen binding protein of claim 7 wherein the Fc domain comprises a half-life extending mutation of set of mutations.
9 . The multispecific antigen binding protein of claim 8 wherein the Fc domain comprises M252Y, S254T and T256E.
10 . The multispecific antigen binding protein of claim 7 wherein the Fc domain has reduced effector function.
11 . The multispecific antigen binding protein of claim 10 wherein said Fc domain comprises the amino acid substitutions L235A and G237A (EU index numbering).
12 . The multispecific antigen binding protein of claim 7 wherein the Fc domain comprises Azymetric Fc mutations.
13 . The multispecific antigen binding protein of claim 4 wherein said multispecific antigen binding protein comprises two kappa light chains and two IgG1 heavy chains.
14 . The multispecific antigen binding protein according to claim 1 wherein said multispecific antigen binding protein comprises:
a. a heavy chain of SEQ ID NO:42, a light chain of SEQ ID NO: 44, a heavy chain of SEQ ID NO: 43, and a light chain of SEQ ID NO:45;
b. a heavy chain of SEQ ID NO:47, a light chain of SEQ ID NO: 49, a heavy chain of SEQ ID NO: 46, and a light chain of SEQ ID NO:48;
c. a heavy chain of SEQ ID NO:50, a light chain of SEQ ID NO: 52, a heavy chain of SEQ ID NO: 51, and a light chain of SEQ ID NO:53; or
d. a heavy chain of SEQ ID NO: 54, a light chain of SEQ ID NO: 56, a heavy chain of SEQ ID NO: 55, and a light chain of SEQ ID NO:57.
15 . The multispecific antigen binding protein of claim 14 wherein said multispecific antigen binding protein comprises a heavy chain of SEQ ID NO: 54, a light chain of SEQ ID NO: 56, a heavy chain of SEQ ID NO: 55, and a light chain of SEQ ID NO:57.
16 . The multispecific antigen binding protein of claim 4 wherein said multispecific antigen binding protein is a bispecific antigen binding protein.
17 . The multispecific antigen binding protein of claim 16 wherein said bispecific antigen binding protein is a bispecific antibody, optionally wherein said bispecific antibody is a Het-mAb.
18 . The multispecific antigen binding protein of claim 1 wherein said multispecific antigen binding protein down-regulates CXCL13 secretion.
19 . The multispecific antigen binding protein of claim 18 wherein said multispecific antigen binding protein down-regulates CXCL13 secretion by greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40% or greater than 45% compared to a negative control antigen binding protein.
20 . A nucleic acid sequence encoding the multispecific antigen binding protein of claim 4 .
21 . A nucleic acid sequence encoding any one, two, three or all four of the following amino acid sequences: a heavy chain of SEQ ID NO: 54, a light chain of SEQ ID NO: 56, a heavy chain of SEQ ID NO: 55, and a light chain of SEQ ID NO:57.
22 . An expression vector comprising the nucleic acid sequence(s) of claim 20 .
23 . A recombinant host cell comprising the nucleic acid sequence according to claim 20 .
24 . A method for the production of a multispecific antigen binding protein, said method comprising culturing the recombinant host cell according to claim 23 under conditions suitable for expression of said nucleic acid sequence, whereby said multispecific antigen binding protein is produced.
25 . A multispecific antigen binding protein produced by the method of claim 24 .
26 . A cell line engineered to express the multispecific antigen binding protein according to claim 4 .
27 . A pharmaceutical composition comprising the multispecific antigen binding protein according to claim 4 and a pharmaceutically acceptable excipient.
28 . A method for the treatment of an immunoinflammatory disease (IBD) in a human subject in need thereof comprising administering to said subject a therapeutically effective amount of the multispecific antigen binding protein according to claim 4 .
29 . A method for the treatment of inflammatory bowel disease (IBD) in a human subject in need thereof comprising administering to said subject a therapeutically effective amount of the pharmaceutical composition according to claim 27 .
30 . (canceled)