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

被引:20
|
作者
Xiang, Hong [1 ,2 ]
Chan, Abigael G. [1 ,3 ]
Ahene, Ago [1 ,4 ]
Bellovin, David I. [1 ,4 ]
Deng, Rong [5 ]
Hsu, Amy W. [1 ,6 ]
Jeffry, Ursula [1 ,7 ]
Palencia, Servando [1 ,8 ]
Powers, Janine [1 ,9 ]
Zanghi, James [1 ,10 ]
Collins, Helen [1 ,11 ]
机构
[1] Five Prime Therapeut Inc, San Francisco, CA USA
[2] Amgen Inc, Clin Pharmacol Modeling & Simulat, Thousand Oaks, CA 91320 USA
[3] Zai Lab US LLC, Global Project Management, Menlo Pk, CA USA
[4] Amgen Inc, Bioanalyt Sci, San Francisco, CA USA
[5] R&D Q Pharm Consulting LLC, Pleasanton, CA USA
[6] Merck & Co Inc, Res, San Francisco, CA USA
[7] NGM Biopharmaceut Inc, Toxicol Dept, San Francisco, CA USA
[8] Teva Pharmaceut, Res, Redwood City, CA USA
[9] Nurix Therapeut, Translat Med, San Francisco, CA USA
[10] Genentech Inc, Bioanalyt Sci, San Francisco, CA 94080 USA
[11] Amgen Inc, Clin, San Francisco, CA USA
关键词
Bemarituzumab; anti-FGFR2b antibody; fibroblast growth factor receptor; pharmacokinetics; toxicology; afucosylated antibody; antibody-dependent cell-mediated cytoxicity; phosphorylation in vitro; cell proliferation in vitro; anti-tumor efficacy; FIBROBLAST-GROWTH-FACTOR-RECEPTOR-2 GENE AMPLIFICATION; K-SAM; GROWTH; RECEPTOR; PHARMACOKINETICS; FGFR2; MAINTENANCE; EXPRESSION;
D O I
10.1080/19420862.2021.1981202
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
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页数:16
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