Abstract 1407: FPA144, a therapeutic monoclonal antibody targeting the FGFR2b receptor, promotes antibody dependent cell-mediated cytotoxicity and stimulates sensitivity to PD-1 in the 4T1 syngeneic tumor model
Authors: Powers Janine , Palencia Servando , Foy Susan , Sennino Barbara , Hidalgo Toni Rose , Gemo Abigael , Brennan Thomas , Pierce Kisten 
Published: July 2016

Five Prime Therapeutics, Inc. has developed an FGFR2b-specific humanized monoclonal antibody, FPA144, to treat patients with cancer bearing overexpression of the FGFR2b receptor, and is currently in clinical trials as a single agent for gastric cancer (NCT02318329). FGFR2 gene amplification and FGFR2b overexpression occur in approximately 5% of gastric cancers and are associated with a poor prognosis in gastric cancer patients. In addition to blocking ligand binding and inducing FGFR2b internalization, FPA144 is glycoengineered for enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). We have shown previously that FPA144 can produce complete and durable tumor growth inhibition in FGFR2b-over-expressing and FGFR2-amplified gastric cancer xenografts in immune-compromised mice (Gemo et al., Poster 5446, AACR 2014). In order to understand the contribution of the immune system to the mechanisms of action of FPA144, we evaluated the anti-tumor effects and immune cell recruitment of FPA144 in the 4T1 model of cancer in immune-competent mice. Although this model expresses FGFR2b, it is not FGFR2 amplified. Therapeutic treatment with FPA144 in the orthotopic 4T1 model resulted in a reduction in tumor burden (33%, P&lt;0.001) and concomitant recruitment of NK cells to the site of tumor implantation, while a modified antibody lacking Fc effector function neither inhibited tumor growth nor lead to the recruitment of NK cells. Together these data support a potential role for ADCC as a mechanism of FPA144 tumor growth inhibition. In addition, treatment with FPA144 increased PD-L1 expressing cells within the tumor microenvironment, providing a strong rationale that FPA144 may combine effectively with PD-1 blockade for additional tumor growth inhibition. PD-1 blockade by the RPM1-14 antibody did not inhibit tumor growth as a single agent in the 4T1 model. Treatment with RPM1-14 in combination with FPA144, however, inhibited tumor growth by 49% (P&lt;0.001), demonstrating an additive benefit of combination therapy. Overall, these data suggest that the enhanced ADCC activity of FPA144 may be critical for anti-tumor efficacy in tumors that have modest expression of FGFR2b. In addition, FPA144 may reprogram the tumor micro-environment in a way that primes the tumor for additional anti-tumor activity when combined with PD-1 blockade.

Citation Format: Janine Powers, Servando Palencia, Susan Foy, Barbara Sennino, Toni Rose Hidalgo, Abigael Gemo, Thomas Brennan, Kisten Pierce. FPA144, a therapeutic monoclonal antibody targeting the FGFR2b receptor, promotes antibody dependent cell-mediated cytotoxicity and stimulates sensitivity to PD-1 in the 4T1 syngeneic tumor model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1407.