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Xiang H, Chan AG, Ahene A, et al. Preclinical characterization of bemarituzumab, an anti-FGFR2b antibody for the treatment of cancer. MAbs. 2021;13(1):1981202doi: 10.1080/19420862.2021.1981202.
Xiang, H., Chan, A. G., Ahene, A., Bellovin, D. I., Deng, R., Hsu, A. W., Jeffry, U., Palencia, S., Powers, J., Zanghi, J., & Collins, H. (2021). Preclinical characterization of bemarituzumab, an anti-FGFR2b antibody for the treatment of cancer. mAbs, 13(1), 1981202. https://doi.org/10.1080/19420862.2021.1981202
Xiang, Hong, et al. "Preclinical characterization of bemarituzumab, an anti-FGFR2b antibody for the treatment of cancer." mAbs vol. 13,1 (2021): 1981202. doi: https://doi.org/10.1080/19420862.2021.1981202
Xiang H, Chan AG, Ahene A, Bellovin DI, Deng R, Hsu AW, Jeffry U, Palencia S, Powers J, Zanghi J, Collins H. 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. PMID: 34719330; PMCID: PMC8565817.
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MAbs. 2021 Jan-Dec;13(1):1981202. doi: 10.1080/19420862.2021.1981202.

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

mAbs

Hong Xiang, Abigael G Chan, Ago Ahene, David I Bellovin, Rong Deng, Amy W Hsu, Ursula Jeffry, Servando Palencia, Janine Powers, James Zanghi, Helen Collins

Affiliations

  1. Five Prime Therapeutics, Inc, South San Francisco, California.
  2. Clinical Pharmacology, Modeling and Simulation, Amgen Inc, Thousand Oaks, California.
  3. Global Project Management, Zai Lab (US) LLC, Menlo Park, California.
  4. Bioanalytic Sciences, Amgen Inc, South San Francisco, California.
  5. R&D Q-Pharm Consulting LLC, Pleasanton.
  6. Research, Merck & Co., Inc, South San Francisco, California.
  7. Toxicology Department, NGM Biopharmaceuticals, Inc, San Francisco, California.
  8. Research, Teva Pharmaceuticals, Redwood city, California.
  9. Translational Medicine, Nurix Therapeutics, San Francisco, California.
  10. Bioanalytic Sciences, Genentech Inc., South San Francisco, California.
  11. Clinic, Amgen Inc., South San Francisco, California.

PMID: 34719330 PMCID: PMC8565817 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

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