National Research Council of Canada

Gilead Sciences, Inc.

Zymeworks Inc.

Maureen D O'Connor-McCourt

Traian Sulea

Jason Baardsnes

John C Zwaagstra

Maria L Jaramillo

Anne E G Lenferink

Myriam Banville

Renald Gilbert

Bruno Gaillet

Ilia Alexandre Tikhomirov

Suzanne Grothe

Catherine Collins

Christiane Cantin

Anne Eg Lenferink

Jason Baarsdness

Gordon Yiu Kon Ng

Adam Louis Corper

Feng Ni

Anders Ohrn

Dmitri Tolkatchev

Yang-Chieh Chou

Antonios Samiotakis

Rana Filfil

Maria Jaramillo

Herein described are antibodies to epidermal growth factor receptor (EGER) having an EGER binding affinity that is sufficient to kill disease cells presenting EGFR at high density, but is insufficient for binding to normal cells. A therapeutic effect is thus achieved while avoiding adverse events that result from unintended binding to normal cells.

Antibodies selective for cells presenting EGFR at high density

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.

TGF-β-receptor ectodomain fusion molecules and uses thereof

Herein described are antibodies to epidermal growth factor receptor (EGFR) having an EGFR binding affinity that is sufficient to kill disease cells presenting EGFR at high density, but is insufficient for binding to normal cells. A therapeutic effect is thus achieved while avoiding adverse events that result from unintended binding to normal cells.

An erbB2 antibody is provided that binds preferentially to disease cells having an erbB2 density greater than a normal erbB2 density. The erbB2 antibody comprises a heavy chain and a light chain. Each chain has a constant region and a variable region. Each variable region comprises framework regions and complementarity determining regions (CDRs), wherein the CDRs have an amino acid sequence set forth below: For the heavy chain: CDR1 GFNIKDTYIH (SEQ ID No. 1) CDR2 RIYPTNGYTRYADSVKG (SEQ ID No. 2) CDR3 WGGDGFYAMDY (SEQ ID No. 3) For the light chain: CDR1 RASQDVNTAVA (SEQ ID No. 4) CDR2 SASFLYS (SEQ ID No. 5) CDR3 QQHYTTPPT (SEQ ID No. 6). At least one of Y57, R59, N30, F53, and Y92 is substituted by an amino acid that confers on said antibody a reduced erbB2 binding affinity (Kd) that is in the range from 0.1 nM to 100 nM. The substitution is other than N30A, F53N, Y92A and Y92F when there is a single substitution in the antibody light chain.

Antibodies selective for cells presenting ErbB2 at high density

Provided is a method of quantitatively determining the ability of individual IgG heavy chains to selectively pair with a particular IgG light chain when the heavy chains and two unique light chains are co-expressed. The method provides results with reasonable throughput and is robust and accurate. The co-expressed heavy and light chains do not need to be isolated and purified which enables more efficient screening.

Methods of quantitating heavy and light chain polypeptide pairs

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.

Peptides are disclosed that are useful for molecular imaging or diagnosis of a disease state, such as cancer, in which clusterin is upregulated.

Peptide ligands for clusterin and uses thereof

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:

Antibodies which target clusterin, a protein involved in the epithelial-to-mesenchymal transition of carcinoma cells, are identified and characterized. The antibodies may be used to modulate tumor cell activity through binding the clusterin.

Methods and compositions for modulating tumor cell activity

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

Antibodies which target clusterin, a protein involved in the epithelial-to-mesenchymal transition of carcinoma cells, are identified and characterized. The antibodies may be used to modulate tumour cell activity through binding to clusterin.

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Beaconsfield, Canada

Maureen D O'Connor-McCourt