ANTAGONISTS OF LIGANDS AND USES THEREOF

摘要

The invention provides multivalent ligand binging agents (traps) for members of the TGF-ß superfamily and polypeptide linkers and methods for making and using such constructs. In an embodiment of the invention there is provided a multivalent binding agent with affinity for a member of the TGF-ß superfamily, said agent comprising the general structure I: (-LINKER1 )_k-[{-linker2--LINKER3_f-}_n-()_m-(linker4-)_d]_h, where: - n and h are independently greater than or equal to 1; - d, f, m and k are independently equal to or greater than zero; - bd1, bd2, bd3 and bd4 are polypeptide binding domains having an affinity for the same member of the TGF-ß superfamily, with bd1, bd2, bd3, and bd4 being independently the same or different from each other; and, -linkeri, Iinker2, Iinker3 and Iinker4 are unstructured polypeptide sequences; wherein the number of amino acids in each linker is determined independently and is greater than or equal to X/2.5; where, X equals the shortest linear distance between: (a) the C-terminus of an isolated form of the binding domain that is located at the N- terminus of the linker and that is specifically bound to its ligand; and, (b) the N-terminus of an isolated form of the binding domain that is located at the C- terminus of the linker and that is specifically bound to its ligand.