National Research Council of Canada

Gilead Sciences, Inc.

Zymeworks Inc.

Me Therapeutics Inc.

Jason Baardsnes

Traian Sulea

Maureen D O'Connor-McCourt

John C Zwaagstra

Maria L Jaramillo

Renald Gilbert

Bruno Gaillet

Ilia Alexandre Tikhomirov

Myriam Banville

Suzanne Grothe

Gordon Yiu Kon Ng

Adam Louis Corper

Anders Ohrn

Salim Dhanji

Enrico O Purisima

Yang-Chieh Chou

Catherine Collins

John Priatel

Christopher R Corbeil

Nazanin Larijani Rohani

Kenneth Harder

Antonios Samiotakis

Gordon Yiu Ng

Maureen O'connor-Mccourt

Maria Jaramillo

Maureen O'CONNOR-Mccourt

Maureen D O'CONNOR-Mccourt

The present application discloses methods of making anti-G-CSF antibodies, anti-G-CSF antibodies, methods of screening the activity of anti-G-CSF antibodies, pharmaceutical compositions of anti-G-CSF antibodies, kits containing anti-G-CSF antibodies, and methods of using anti-G-CSF antibodies to treat a disease.

Anti-G-CSF antibodies and uses thereof

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

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

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 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:

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Montreal, Canada

Jason Baardsnes