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A novel monovalent FGFR1 antagonist: Preclinical safety profiles in rodents and non-human primates.
Yu, Ping; Knippel, Anja; Onidi, Manuela; Paoletti, Andrea; Vigna, Enrico; Hellmann, Juergen; Esdar, Christina.
Afiliação
  • Yu P; Global R&D, Merck KGaA, RBM S.p.A, Via Ribes, 1, Colleretto Giacosa, 10010 (TO), Italy. Electronic address: ping.yu@merckgroup.com.
  • Knippel A; Global R&D, Merck KGaA, Frankfurter Straße 250, 64293 Darmstadt, Germany. Electronic address: anja.knippel@merckgroup.com.
  • Onidi M; Global R&D, Merck KGaA, RBM S.p.A, Via Ribes, 1, Colleretto Giacosa, 10010 (TO), Italy. Electronic address: manuela.onidi@merckgroup.com.
  • Paoletti A; Global R&D, Merck KGaA, RBM S.p.A, Via Ribes, 1, Colleretto Giacosa, 10010 (TO), Italy. Electronic address: andrea.paoletti@merckgroup.com.
  • Vigna E; Global R&D, Merck KGaA, RBM S.p.A, Via Ribes, 1, Colleretto Giacosa, 10010 (TO), Italy. Electronic address: enrico.vigna@merckgroup.com.
  • Hellmann J; Global R&D, Merck KGaA, Frankfurter Straße 250, 64293 Darmstadt, Germany. Electronic address: juergen.hellmann@merckgroup.com.
  • Esdar C; Global R&D, Merck KGaA, Frankfurter Straße 250, 64293 Darmstadt, Germany. Electronic address: christina.esdar@merckgroup.com.
Toxicol Appl Pharmacol ; 406: 115215, 2020 11 01.
Article em En | MEDLINE | ID: mdl-32866523
Blocking Fibroblast Growth Factor Receptor 1 (FGFR1) is an attractive therapeutic option for treatment of cancer subtypes with amplification and over-expression of FGFR1. Selective targeting of FGFR1 can be achieved using an antibody-based approach, as small molecule inhibitors may not discriminate between FGFR1, 2, 3 and 4 due to their highly homologous kinase domain. However, development of classical bivalent FGFR1 directed antibodies has failed due to non-tolerated body weight decreases in preclinical species. M6123 is a novel IgG-like monovalent FGFR1 specific binder with enhanced Antibody-Dependent Cellular Cytotoxicity (ADCC) effector function and inhibits tumor growth significantly in FGFR1-dependent human xenograft models without reduced body weight in tumor-bearing mice. Toxicology studies reported here characterized the safety profile of M6123 in mouse, rat, and monkey. There were significant differences among animal species under similar M6123 exposure levels. Rats showed metastatic mineralization with an imbalance in serum phosphate at low doses, while mineralization was not found in mice or monkeys, even though hyperphosphatemia was detected in mice. Subtle differences in calcium/phosphate homoeostasis feedback loops may trigger the susceptibility to mineralization among animal species; nevertheless, the exact mechanism remains unknown. Monkeys showed marked, but reversible, decreases in peripheral blood NK cells and neutrophils. The latter was associated with considerably increased neutrophilic infiltrates in the liver sinusoids and red pulp of the spleen. These effects in monkeys are likely related to the enhanced ADCC activity of M6123. Overall, M6123 showed a superior safety profile in animals compared to bivalent FGFR1 antagonists or pan-FGFR inhibitors.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores de Proteínas Quinases / Receptor Tipo 1 de Fator de Crescimento de Fibroblastos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: Toxicol Appl Pharmacol Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores de Proteínas Quinases / Receptor Tipo 1 de Fator de Crescimento de Fibroblastos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: Toxicol Appl Pharmacol Ano de publicação: 2020 Tipo de documento: Article