National Research Council of Canada

John C Zwaagstra

Traian Sulea

Maureen D O'Connor-McCourt

Jason Baardsnes

Maria L Jaramillo

Anne E G Lenferink

Myriam Banville

Catherine Collins

Enrico O Purisima

Maureen D O'Connor

Gregory De Crescenzo

Maureen D O'Conner

Beatrice Paul-Roc

Christopher R Corbeil

Nazanin Larijani Rohani

Maureen D O'Connor-Mccourt

Maureen D O'CONNOR-Mccourt

Jason Baarsdness

The present invention is directed to anti-Her2 antibodies and fragments thereof, compositions, and uses thereof. The antibodies and fragments thereof bind to Her2-expressing cells in a pH-dependent manner, with low affinity at the physiological pH typical of normal cells and tissues, and with high affinity at the slightly acidic pH characteristic to solid tumors. Furthermore, the antibodies inhibit the growth of tumor spheroids at a level comparable to that of the benchmark anti-Her2 antibody Herceptin at acidic pH, whereas these effects were significantly reduced at physiological pH. This pH selectivity of cellular growth inhibition is maintained upon antibody conjugation to cytotoxic drugs. The invention also includes methods of treating solid tumors, methods of detecting solid tumors, and methods of pH-dependent capturing of the Her-2 ectodomain.

Antibody variants with pH-dependent antigen binding for selective targeting of solid tumors

The present invention relates, in general, to polypeptides capable of binding and neutralizing transforming growth factor beta (TGF-beta) ligands, and uses of these polypeptides for treating disorders related to TGF-beta expression or activation (e.g. cancer and fibrotic diseases), and methods of making such molecules.

TGF-β-receptor ectodomain fusion molecules and uses thereof

The present invention relates, in general, to polypeptides capable of binding and neutralizing transforming growth factor beta (TGF-β) ligands, and uses of these polypeptides for treating disorders related to TGF-beta expression or activation (e.g. cancer and fibrotic diseases), and methods of making such molecules.

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 multivalent ligand binding agents (traps) for members of the TGF-&#x3b2; superfamily and polypeptide linkers and methods for making and using such constructs. The traps may be used as therapeutic or diagnostic (imaging or non-imaging) agents for diseases/disorders caused by over-production/activity of the target ligand. In an embodiment of the invention there is provided a multivalent binding agent with affinity for a member of the TGF-&#x3b2; superfamily, the agent having the general structure I:(&#x3c;bd1&#x3e;-linker1)-[{&#x3c;bd1&#x3e;-linker2-&#x3c;bd2&#x3e;-linker3-}-(&#x3c;bd3&#x3e;)-(linker4-&#x3c;bd4&#x3e;)],where:

Antagonists of ligands and uses thereof

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.

The invention provides multivalent ligand binding agents (traps) for members of the TGF-&#x3b2; superfamily and polypeptide linkers and methods for making and using such constructs. The traps may be used as therapeutic or diagnostic (imaging or non-imaging) agents for diseases/disorders caused by over-production/activity of the target ligand. In an embodiment of the invention there is provided a multivalent binding agent with affinity for a member of the TGF-&#x3b2; superfamily, the agent having the general structure I:(&#x3c;1&#x3e;-linker1)-[{&#x3c;1&#x3e;-linker2-&#x3c;2&#x3e;-linker3-}-(&#x3c;3&#x3e;)-(linker4-&#x3c;4&#x3e;)],where:

The invention provides multivalent ligand binding agents (traps) for members of the TGF-&#x3b2; superfamily and polypeptide linkers and methods for making and using such constructs. The traps may be used as therapeutic or diagnostic (imaging or non-imaging) agents for diseases/disorders caused by over-production/activity of the target ligand. In an embodiment of the invention there is provided a multivalent binding agent with affinity for a member of the TGF-&#x3b2; superfamily, the agent having the general structure I:(&#x3c;bd1&#x3e;-linker1)-[{&#x3c;bd1&#x3e;-linker2-&#x3c;bd2&#x3e;linker3-}-(&#x3c;bd3&#x3e;)-(linker4-&#x3c;bd4&#x3e;)],where:

Antagonist of ligands and uses thereof

Fusion proteins and coiled-coil induced dimers prepared from both the ectodomains and the kinase domains are disclosed. The receptor domains when presented in the form of a homodimer or heterodimer by virtue of the coiled-coil tag have enhanced ligand binding activity or enhanced kinase activity. The kinetics of binding and the antagonistic potencies of the ectodomain dimers, and their use to alter or inhibit signaling is described. Application of the ectodomain and kinase domain dimers in assays for selecting compounds capable of inhibiting ligand binding and kinase activity, respectively, is described.

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Laval, Canada

John C Zwaagstra