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: 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, Ingrid B J K Joseph
• Journal: mAbs (MAbs) 2011 Jul-Aug Vol. 3 Issue 4 Pg. 362-75 ISSN: 1942-0870 [Electronic] United States
• PMID: 21697654 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Cytokine TWEAK
• Ligands
• Receptors, Tumor Necrosis Factor
• TNFRSF12A protein, human
• TNFSF12 protein, human
• TWEAK Receptor
• Tnfrsf12a protein, mouse
• Tumor Necrosis Factors

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, immunology, metabolism, pharmacology)
• Antineoplastic Agents (administration & dosage, immunology, metabolism, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cytokine TWEAK
• HT29 Cells
• Humans
• Ligands
• Mice
• Neoplasms (immunology, therapy)
• Protein Binding
• Receptors, Tumor Necrosis Factor (agonists, immunology, metabolism)
• TWEAK Receptor
• Tumor Necrosis Factors (immunology, metabolism)
• Xenograft Model Antitumor Assays