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Conformational stability and aggregation of therapeutic monoclonal antibodies studied with ANS and thioflavin T binding

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Development of an Fn14 agonistic antibody as an anti-tumor agent

Content Provider	PubMed Central
Author	Michaelson, Jennifer S. Amatucci, Aldo Kelly, Rebecca Su, Lihe Garber, Ellen Day, Eric S. Berquist, Lisa Cho, Sandy Li, You Parr, Michael Willen, Laure Schneider, Pascal Wortham, Kathleen Burkly, Linda C. Hsu, Yen-ming Joseph, Ingrid Bjk
Copyright Year	2011
Abstract	TNF-like weak inducer of apoptosis (TWEAK), a tumor necrosis factor (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 upregulated 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 BIIB036 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 or tumor killing activity caused by antibody-dependent cell-mediated cytotoxicity. 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.
Related Links	http://dx.doi.org/10.4161/mabs.3.4.16090
Ending Page	375
Page Count	14
Starting Page	362
File Format	PDF
ISSN	19420862
e-ISSN	19420870
Journal	mAbs
Issue Number	4
Volume Number	3
Language	English
Publisher	Landes Bioscience
Publisher Date	2011-07-01
Access Restriction	Open
Rights Holder	Landes Bioscience
Subject Keyword	Immunology Immunology and Allergy Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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