Abstract 2136: Inhibiting cancer growth by targeting the TNFR2 oncogene with TNFR2 antagonistic antibodies
Authors: Heather Torrey, John Butterworth, Toshiyuki Mera, Yoshiaki Okubo, Limei Wang, Danielle Baum, Audrey Defusco, Sara Plager, Sarah Warden, Daniel Huang, Eva Vanamee, Rosemary Foster, Denise L. Faustman
Journal: Cancer Research (2017)

Abstract Background: Although antibody targeting of the HER2 oncogene represents an outstanding clinical treatment and a success story showing direct cancer killing with antibodies, many oncogenes are intracellular and are not expressed broadly, whether on a single or multiple tumor types. The recently discovered TNFR2 oncogene is broadly expressed on many human tumors. Colon cancer cells, multiple myeloma cells, renal cell carcinoma cells, Hodgkin’s lymphoma cells, ovarian cancer epithelial cells and cutaneous non-Hodgkin’s lymphoma cells can aberrantly express the TNFR2 receptor as an oncogene for growth. For non-cutaneous T cell lymphomas, the genetic basis of the TNFR2 deregulation has recently been tied to constitutive overexpression of TNFR2 from frequent gene duplications or cytoplasmic TNFR2 mutations that confer constitutive agonism, i.e. tumor expansion. These features make TNFR2 an advantageous molecular target for direct tumor targeting. Methods: We designed monoclonal antibodies to target the TNFR2 oncogene and directly kill human tumor cells. TNFR2-directed antibodies were screened for their ability to induce the death of rapidly growing tumor cells, such as ovarian cancer cells (i.e., OVCAR3). Results: Novel dominant anti-TNFR2 antibody candidates (TNFR2 antagonistic antibodies) did not require Fc binding for activity, expressed dominance over TNF-mediated agonism, and hampered intracellular NF-κB activation and phosphorylation obligatory for TNFR2 signaling and cell growth of tumor cells. Even low doses of TNFR2 antagonists rapidly and directly killed TNFR2 oncogene-expressing ovarian cancer cells. Examination of the structural biology of these dominant TNFR2 antagonist antibodies uncovered a unique and stabilizing TNFR2 receptor formation, anti-parallel dimeric TNFR2, which inhibits intracellular signaling, cannot bind TNF, cannot be cleaved to create soluble TNFR2 and is exponentially more active on the dividing cells of cancer. Conclusions: TNFR2 is a unique and broadly expressed human oncogene that can potentially be targeted to directly stop the growth of cancer cells (including ovarian cancer cells) by antibody-induced cell death. The creation of dominant TNFR2 antagonism provides a unique, non-signaling complex that has implications for the therapeutic targeting of TNF superfamily receptors, especially TNFR2. Citation Format: Heather Torrey, John Butterworth, Toshiyuki Mera, Yoshiaki Okubo, Limei Wang, Danielle Baum, Audrey Defusco, Sara Plager, Sarah Warden, Daniel Huang, Eva Vanamee, Rosemary Foster, Denise L. Faustman. Inhibiting cancer growth by targeting the TNFR2 oncogene with TNFR2 antagonistic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2136. doi:10.1158/1538-7445.AM2017-2136