Abstract LB539: Development of GB2102, a novel and highly differentiated anti-FGFR2b antibody for the treatment of gastric cancer

Abstract

Abstract Background: Gastric cancer (GC) is a complex and heterogeneous disease with limited available treatment options. Fibroblast growth factor receptor-2b (FGFR2b) is overexpressed in approximately 2-30% of GC and associated with worse prognosis. Bemarituzumab is an afucosylated humanized monoclonal antibody that specifically inhibits FGFR2b. In the FIGHT trial, bemarituzumab showed beneficial response in GC, but appeared to cause high corneal adverse events. It was hypothesized that FGF10 inhibition may be the mechanism of corneal toxicity by bemarituzumab. We have recently generated a monoclonal antibody against FGFR2b with potent FGF7 blocking activity but weak inhibition activity for FGF10. Thus, GB2102 may represent a differentiated antibody therapeutics that has a potential to decrease the adverse effects in the eyes. Methods: GB2102 was generated by immunization of FGFR2b protein in mice followed by hybridoma technique. FGF7 and FGF10 ligand blocking was assessed by ELISA. FGF7-induced FGFR2b phosphorylation and cell proliferation were studied in SNU-16 gastric cancer tumor cell line. Antibody-dependent cell-mediated cytotoxicity (ADCC) function was evaluated by IL-2-activated NK cell-induced lysis of target cells. Results: GB2102 displayed potent blocking of FGF7-FGFR2b pathway by inhibition of FGF7-induced FGFR2b phosphorylation and tumor cell proliferation. But GB2102 showed weak blocking of FGF10 binding to FGFR2b compared with benchmark, suggesting that GB2102 may have better safety profile in corneal toxicity. In ADCC function assay, GB2102 induced potent ADCC effects by primary human NK cells to kill FGFR2b-expressing tumor cells. Conclusions: In summary, preclinical studies showed that GB2102 is an anti-FGFR2b antibody with potent ADCC effect and strong FGF7 blocking but weak FGF10 inhibition. These results suggest that GB2102 is potentially a safe and effective candidate for the treatment of FGFR2b positive gastric cancer. Citation Format: Tiantian Zhou, Qinglin Du, Xueyan Yang, Fei Peng, James Li, Shuhua Han. Development of GB2102, a novel and highly differentiated anti-FGFR2b antibody for the treatment of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB539.