National Research Council of Canada

Catherine Collins

Traian Sulea

Maureen D O'Connor-McCourt

John C Zwaagstra

Jason Baardsnes

Maria L Jaramillo

Myriam Banville

The present invention addresses limitations of prior art receptor-based traps through a methodology called the clamp/click/cleave (CCC) approach. Two fusion proteins each comprising a binding domain fused to a coiled-coil are non-covalently dimerized through the coiled-coil (clamp), and the dimer so formed is stabilized by a covalent disulphide bond (click) between cysteine residues located on the fusion proteins between the binding domains and coiled-coils. Once the disulphide bond has formed, the coiled-coils are subsequently removed (cleave) by cleaving the fusions proteins at cleavage sites located between the cysteine residues and the coiled-coils to provide the covalently dimerized bivalent binding agent of the present invention. Such binding agents are useful in the treatment and diagnosis of disease states characterized by production and/or overexpression of a ligand to which the binding domains bind. The invention is particularly useful for covalently dimerized receptor-based ligand traps where the binding domains are receptor ligand-binding domains, such as those of TGF-&#x3b2; receptors.

Covalently dimerized bivalent binding agents

The invention provides hetero-multivalent ligand binging agents (traps) for members of the TGF-&#x3b2; superfamily, as well as methods for making and using such constructs. In an embodiment of the invention there is provided a hetero-multivalent binding agent with affinity for a member of the TGF-&#x3b2; superfamily. The agent comprises the general structure I:(&#x3c;bd1&#x3e;-linker1)-[{&#x3c;bd1&#x3e;-linker2-&#x3c;bd2&#x3e;-linker3-}-(&#x3c;bd3&#x3e;)-(linker4-&#x3c;bd4&#x3e;)],where bd1, bd2, bd3 and bd4 are polypeptide binding domains having an affinity for different sites on the same member or for different members of the TGF-&#x3b2; superfamily; at least two of bd1, bd2, bd3, and bd4 are different from each other.

Antagonists of ligands and uses thereof

Growing community of inventors

Dorval, Canada

Catherine Collins