Engineering and development of a novel bispecific ADC targeting EGFR and FGFR2b

EGFR is a clinically validated oncogenic driver frequently overexpressed in gastric cancer. Fibroblast growth factor receptor 2b (FGFR2b), a transmembrane receptor tyrosine kinase,is likewise overexpressed in approximately 30% of gastric and gastroesophageal junction (GEJ) cancers, and is associated with poor prognosis. Notably, subsets of gastric tumors co‑express EGFR and FGFR2b, indicating potential cooperative signaling that contributes to tumor progression and therapeutic resistance. Bemarituzumab, an afucosylated FGFR2b monoclonal antibody has shown efficacy in the clinical study for the treatment in patients with FGFR2b‑positive GC and GEJ cancer. However, the clinical application of bemarituzumab is accompanied by safety concerns. The corneal adverse events were frequently observed. Co-expression of EGFR and FGFR2b presents an attractive opportunity for a dual targeting strategy and supports the bispecific design that could potentially address the safety issues. In this study, we developed several bispecific antibodies (bsAb) targeting EGFR and FGFR2b. These bsAb demonstrated enhanced binding avidity and superior internalization efficiency compared with bemarituzumab and BG‑C137 mAb analogs in EGFR⁺/FGFR2b⁺ dual expressing cancer cell lines. Our EGFR×FGFR2b bsAb function as a partial FGFR2b ligand blocker, and only weakly inhibiting FGF7 while sparing FGF10‑mediated signaling, thus with the potential to reduce on‑target toxicity associated with FGF7/FGF10 blockade. Several bsAb ADC were generated with various cytotoxic payloads and are being tested in vitro and in vivo studies.