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

MAbs. 2021 Jan-Dec;13(1):1981202. doi: 10.1080/19420862.2021.1981202.

Abstract

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.

Keywords: Bemarituzumab; afucosylated antibody; antibody-dependent cell-mediated cytoxicity; phosphorylation in vitro; anti-FGFR2b antibody; anti-tumor efficacy; cell proliferation in vitro; fibroblast growth factor receptor; pharmacokinetics; toxicology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacokinetics
  • Antibody-Dependent Cell Cytotoxicity
  • Cell Line, Tumor
  • Mice
  • Rats
  • Receptor, Fibroblast Growth Factor, Type 2* / metabolism
  • Receptor, Fibroblast Growth Factor, Type 2* / therapeutic use
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / pathology

Substances

  • Antibodies, Monoclonal, Humanized
  • Receptor, Fibroblast Growth Factor, Type 2
  • bemarituzumab

Grants and funding

This work was funded by Five Prime Therapeutics, Inc.