RG7212 anti-TWEAK mAb inhibits tumor growth through inhibition of tumor cell proliferation and survival signaling and by enhancing the host antitumor immune response.

Abstract

PURPOSE:

To explore the role of TWEAK in tumor growth and antitumor immune response and the activity and mechanism of RG7212, an antagonistic anti-TWEAK antibody, in tumor models.

EXPERIMENTAL DESIGN:

TWEAK-induced signaling and gene expression were explored in tumor cell lines and inhibition of these effects and antitumor efficacy with RG7212 treatment was assessed in human tumor xenograft-, patient-derived xenograft, and syngeneic tumor models and phase I patients. Genetic features correlated with antitumor activity were characterized.

RESULTS:

In tumor cell lines, TWEAK induces proliferation, survival, and NF-κB signaling and gene expression that promote tumor growth and suppress antitumor immune responses. TWEAK-inducible CD274, CCL2, CXCL-10 and -11 modulate T-cell and monocyte recruitment, T-cell activation, and macrophage differentiation. These factors and TWEAK-induced signaling were decreased, and tumor, blood, and spleen immune cell composition was altered with RG7212 treatment in mice. RG7212 inhibits tumor growth in vivo in models with TWEAK receptor, Fn14, expression, and markers of pathway activation. In phase I testing, signs of tumor shrinkage and stable disease were observed without dose-limiting toxicity. In a patient with advanced, Fn14-positive, malignant melanoma with evidence of tumor regression, proliferation markers were dramatically reduced, tumor T-cell infiltration increased, and tumor macrophage content decreased. Antitumor activity, a lack of toxicity in humans and animals and no evidence of antagonism with standard of care or targeted agents in mice, suggests that RG7212 is a promising agent for use in combination therapies in patients with Fn14-positive tumors.

• Authors: Xuefeng Yin, Leopoldo Luistro, Hua Zhong, Melissa Smith, Tom Nevins, Kathleen Schostack, Holly Hilton, Tai-An Lin, Theresa Truitt, Denise Biondi, Xiaoqian Wang, Kathryn Packman, Jim Rosinski, Windy Berkofsky-Fessler, Jian-Ping Tang, Saumya Pant, David Geho, Suzana Vega-Harring, Mark Demario, Hy Levitsky, Mary Simcox
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 20 Pg. 5686-98 (Oct 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23974006 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Cytokine TWEAK
• TNFSF12 protein, human
• Tumor Necrosis Factor Inhibitors
• Tumor Necrosis Factors

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cytokine TWEAK
• Disease Models, Animal
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Neoplasms (genetics, immunology, metabolism, pathology)
• Signal Transduction (drug effects)
• Tumor Burden (drug effects)
• Tumor Microenvironment (drug effects, genetics, immunology)
• Tumor Necrosis Factor Inhibitors
• Tumor Necrosis Factors (metabolism)
• Xenograft Model Antitumor Assays