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Authors: Jennifer S. Michaelson, Aldo Amatucci, Rebecca Kelly, Lihe Su, Ellen Garber, Eric S. Day, Lisa Berquist, Sandy Cho, You Li, Michael Parr, Laure Wille, Pascal Schneider, Kathleen Wortham, Linda C. Burkly, Yen-Ming Hsu and Ingrid B.J.K. Joseph

Jennifer S. Michaelson

Corresponding author: jennifer.michaelson@biogenidec.com
Molecular Discovery, Biogen Idec, 12 Cambridge Center; Cambridge, MA USA

Aldo Amatucci

Molecular Discovery, Biogen Idec, 12 Cambridge Center; Cambridge, MA USA

Rebecca Kelly

Molecular Discovery, Biogen Idec, 12 Cambridge Center; Cambridge, MA USA

Lihe Su

Molecular Discovery, Biogen Idec, 12 Cambridge Center; Cambridge, MA USA

Ellen Garber

Molecular Discovery, Biogen Idec, 12 Cambridge Center; Cambridge, MA USA

Eric S. Day

Molecular Discovery, Biogen Idec, 12 Cambridge Center; Cambridge, MA USA

Lisa Berquist

Molecular Discovery, Biogen Idec, 12 Cambridge Center; Cambridge, MA USA

Sandy Cho

Molecular Discovery, Biogen Idec, 12 Cambridge Center; Cambridge, MA USA

You Li

Molecular Discovery, Biogen Idec, 12 Cambridge Center; Cambridge, MA USA

Michael Parr

Molecular Discovery, Biogen Idec, 12 Cambridge Center; Cambridge, MA USA

Laure Wille

Department of Biochemistry, University of Lausanne; Lausanne, Switzerland

Pascal Schneider

Department of Biochemistry, University of Lausanne; Lausanne, Switzerland

Kathleen Wortham

Molecular Discovery, Biogen Idec, 12 Cambridge Center; Cambridge, MA USA

Linda C. Burkly

Molecular Discovery, Biogen Idec, 12 Cambridge Center; Cambridge, MA USA

Yen-Ming Hsu

Molecular Discovery, Biogen Idec, 12 Cambridge Center; Cambridge, MA USA

Ingrid B.J.K. Joseph

Molecular Discovery, Biogen Idec, 12 Cambridge Center; Cambridge, MA USA

Abstract:
TWEAK, a TNF family ligand with pleiotropic cellular functions, was originally described as capable of inducing tumor cell death in vitro. TWEAK functions by binding its receptor, Fn14, which is up-regulated on many human solid tumors. Herein, we show that intratumoral administration of TWEAK, delivered either by an adenoviral vector or in an immunoglobulin Fc-fusion form, results in significant inhibition of tumor growth in a breast xenograft model. To exploit the TWEAK-Fn14 pathway as a therapeutic target in oncology, we developed an anti-Fn14 agonistic antibody, BIIB036. Studies described herein show that BIIB036 binds specifically to Fn14 but not other members of the TNF receptor family, induces Fn14 signaling, and promotes tumor cell apoptosis in vitro. In vivo, BIIB036 effectively inhibits growth of tumors in multiple xenograft models, including colon (WiDr), breast (MDA-MB-231), and gastric (NCI-N87) tumors, regardless of tumor cell growth inhibition response observed to BIIB036 in vitro. The anti-tumor activity in these cell lines is not TNF-dependent. Increasing the antigen-binding valency of BIB036 significantly enhances its anti-tumor effect, suggesting the contribution of higher order cross-linking of the Fn14 receptor. Full Fc effector function is required for maximal activity of BIIB036 in vivo, likely due to the cross-linking effect and/or ADCC mediated tumor killing activity. Taken together, the anti-tumor properties of BIIB036 validate Fn14 as a promising target in oncology and demonstrate its potential therapeutic utility in multiple solid tumor indications.

Received: June 22, 2011; Accepted: May 17, 2011

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