Preclinical characterization of bemarituzumab, an anti-FGFR2b antibody for the treatment of cancer

• Published in: mAbs Vol. 13; no. 1; p. 1981202
• Main Authors: Xiang, Hong, Chan, Abigael G, Ahene, Ago, Bellovin, David I, Deng, Rong, Hsu, Amy W, Jeffry, Ursula, Palencia, Servando, Powers, Janine, Zanghi, James, Collins, Helen
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01-01-2021; Taylor & Francis Group
• Subjects: afucosylated antibody; antibody-dependent cell-mediated cytoxicity; phosphorylation in vitro; anti-FGFR2b antibody; Bemarituzumab; fibroblast growth factor receptor; pharmacokinetics; toxicology; toxicology; anti-FGFR2b antibody; cell proliferation in vitro; fibroblast growth factor receptor; anti-tumor efficacy; pharmacokinetics; Bemarituzumab; afucosylated antibody; antibody-dependent cell-mediated cytoxicity; phosphorylation in vitro
• ISSN: 1942-0862; 1942-0870
• DOI: 10.1080/19420862.2021.1981202

Bemarituzumab (FPA144) is a first-in-class, humanized, afucosylated immunoglobulin G1 monoclonal antibody (mAb) directed against fibroblast growth factor receptor 2b (FGFR2b) with two mechanisms of action against FGFR2b-overexpressing tumors: inhibition of FGFR2b signaling and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). Bemarituzumab is being developed as a cancer therapeutic, and we summarize here the key nonclinical data that supported moving it into clinical trials. Bemarituzumab displayed sub-nanomolar cross-species affinity for FGFR2b receptors, with >20-fold enhanced binding affinity to human Fc gamma receptor IIIa compared with the fucosylated version. In vitro, bemarituzumab induced potent ADCC against FGFR2b-expressing tumor cells, and inhibited FGFR2 phosphorylation and proliferation of SNU-16 gastric cancer cells in a concentration-dependent manner. In vivo, bemarituzumab inhibited tumor growth through inhibition of the FGFR2b pathway and/or ADCC in mouse models. Bemarituzumab demonstrated enhanced anti-tumor activity in combination with chemotherapy, and due to bemarituzumab-induced natural killer cell-dependent increase in programmed death-ligand 1, also resulted in enhanced anti-tumor activity when combined with an anti-programmed death-1 antibody. Repeat-dose toxicity studies established the highest non-severely-toxic dose at 1 and 100 mg/kg in rats and cynomolgus monkeys, respectively. In pharmacokinetic (PK) studies, bemarituzumab exposure increase was greater than dose-proportional, with the linear clearance in the expected dose range for a mAb. The PK data in cynomolgus monkeys were used to project bemarituzumab linear PK in humans, which were consistent with the observed human Phase 1 data. These key nonclinical studies facilitated the successful advancement of bemarituzumab into the clinic.