National Research Council of Canada

Gilead Sciences, Inc.

Universitéde Montreal

Renald Gilbert

Traian Sulea

Danica Stanimirovic

Maureen D O'Connor-McCourt

Jason Baardsnes

Maria L Jaramillo

Mehdi Arbabi-Ghahroudi

Kristin Kemmerich

Ilia Alexandre Tikhomirov

Bruno Gaillet

Myriam Banville

Suzanne Grothe

Bernard Massie

Marilyne Blain

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

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

Efficient and muscle-specific gene expression can be obtained with constructs containing two or more copies of USE and/or &#x394;USE fused to the minimal promoter of the TnISlow gene. USE is a small (about 160-bp) upstream enhancer of the TnISlow gene that confers slow-twitch muscle fiber specificity. &#x394;USE is generated from a 100-bp deletion at the 5' end of USE. &#x394;USE confers expression in slow- and fast-twitch muscle fibers. The strength and relatively small size (less than 600-bp) of these constructs make them useful for gene therapy applications.

Constructs for enhancement of gene expression in muscle

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Montreal, Canada

Renald Gilbert