Antagonists of IL-6
A binding domain polypeptide and fusion proteins thereof that recognize an IL6/IL6 receptor complex, as well as compositions and methods of use thereof.
1. An isolated polypeptide comprising a binding domain which can specifically bind to a human IL6/IL6R (IL6xR) complex, wherein the binding domain
(a) specifically binds to the human IL6xR complex with a higher affinity than to either human IL6 or human IL6Rα alone;
(b) can compete with a gp130 for binding to a soluble human IL6xR complex; and
(c) comprises an antibody light chain variable region, wherein the antibody light chain variable region comprises CDR1, CDR2, and CDR3 sequences found in amino acids 649-758 of SEQ ID NO:608, and an antibody heavy chain variable region, wherein the antibody heavy chain variable region comprises CDR1, CDR2, and CDR3 sequences found in amino acids 512-631 of SEQ ID NO:608, and wherein the CDRs are defined by the Kabat, Chothia, AbM or contact definition.
2. The polypeptide of claim 1 , wherein the antibody heavy chain variable region is at least 95% identical to amino acids 512-631 of SEQ ID NO:608 and the antibody light chain variable region is at least 95% identical to amino acids 649-758 of SEQ ID NO:608.
3. The polypeptide of claim 1 , wherein the human IL6xR complex has an amino acid sequence consisting of the mature polypeptide sequence of SEQ ID NO:606.
4. The polypeptide of claim 1 , wherein the binding domain does not inhibit signaling of human gp130 family cytokines other than human IL6.
5. The polypeptide of claim 1 , wherein the binding domain comprises an antigen binding domain of an antibody, a scFv, or a Fab.
6. The polypeptide of claim 1 which comprises, from amino-terminus to carboxy-terminus: (i) the binding domain, (ii) a linker, and (iii) an antibody constant region, wherein the constant region comprises an immunoglobulin Fc domain or one or more CH domains of an immunoglobulin Fc domain.
7. The polypeptide of claim 6 , wherein the linker is an immunoglobulin hinge region polypeptide.
8. The polypeptide of claim 6 , wherein the linker is selected from SEQ ID NOs:497-604 or 823-828.
9. The polypeptide of claim 6 , wherein the immunoglobulin Fc domain is an IgG1 Fc domain comprising mutations L234A, L235A, G237A, E318A, K320A, and K322A.
10. The polypeptide of claim 6 , wherein the constant region lacks or has reduced antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement activation and complement-dependent cytotoxicity (CDC), or any combination thereof.
11. The polypeptide of claim 10 , wherein the polypeptide binds to an FcRn receptor.
12. A composition comprising the polypeptide of claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.