title: Development of an Fn14 agonistic antibody as an anti-tumor agent.
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.
authors.affiliation: Molecular Discovery, Biogen Idec, 12 Cambridge Center, Cambridge, MA, USA. Jennifer.Michaelson@biogenidec.com
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Michaelson
authors.forename: Aldo
authors.initials: A
authors.lastname: Amatucci
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kelly
authors.forename: Lihe
authors.initials: L
authors.lastname: Su
authors.forename: Ellen
authors.initials: E
authors.lastname: Garber
authors.forename: Eric S
authors.initials: ES
authors.lastname: Day
authors.forename: Lisa
authors.initials: L
authors.lastname: Berquist
authors.forename: Sandy
authors.initials: S
authors.lastname: Cho
authors.forename: You
authors.initials: Y
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Parr
authors.forename: Laure
authors.initials: L
authors.lastname: Wille
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Kathleen
authors.initials: K
authors.lastname: Wortham
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.forename: Yen-Ming
authors.initials: YM
authors.lastname: Hsu
authors.forename: Ingrid B J K
authors.initials: IB
authors.lastname: Joseph
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D000074049:Cytokine TWEAK; D019073:HT29 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011485:Protein Binding; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists* / Q000276:immunology / Q000378:metabolism; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000276:immunology* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000074049:Cytokine TWEAK; D008024:Ligands; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D048069:Tumor Necrosis Factors