Nonclinical pharmacokinetics, pharmacodynamics and safety assessment of a FLT3L-Fc molecule for cancer immunotherapy.

Autor: Wu KC; Department of Safety Assessment, Genentech Inc., South San Francisco, CA 94080, United States of America., Adedeji AO; Department of Safety Assessment, Genentech Inc., South San Francisco, CA 94080, United States of America., Zabka TS; Department of Safety Assessment, Genentech Inc., South San Francisco, CA 94080, United States of America., Hosseini I; Department of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA 94080, United States of America., Kenkre R; Department of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA 94080, United States of America., Getz JA; Department of Bioanalytical Sciences, Genentech Inc., South San Francisco, CA 94080, United States of America., Nguyen T; Department of Safety Assessment, Genentech Inc., South San Francisco, CA 94080, United States of America., Decalf J; Department of Cancer Immunology, Genentech Inc., South San Francisco, CA 94080, United States of America., Bainbridge TW; Department of Protein Chemistry, Genentech Inc., South San Francisco, CA 94080, United States of America., Chilton JA; Charles River Laboratories, Reno, NV 89511, United States of America., Moussion CC; Department of Cancer Immunology, Genentech Inc., South San Francisco, CA 94080, United States of America., Rao GK; Department of Safety Assessment, Genentech Inc., South San Francisco, CA 94080, United States of America. Electronic address: rao.gautham@gene.com.
Jazyk: angličtina
Zdroj: Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2024 Feb; Vol. 483, pp. 116837. Date of Electronic Publication: 2024 Jan 24.
DOI: 10.1016/j.taap.2024.116837
Abstrakt: FLT3L-Fc is a cytokine-Fc fusion agonizing receptor-type tyrosine-protein kinase FLT3 (fms-related tyrosine kinase 3; CD135). FLT3 is expressed on dendritic cells (DCs) as well as myeloid and lymphoid progenitors. Nonclinical pharmacokinetics, pharmacodynamics and safety of FLT3L-Fc were investigated in rats and cynomolgus monkeys. FLT3L-Fc induced robust pharmacodynamic responses, evidenced by marked expansion of peripheral blood cDC1s, cDC2s, and pDCs (up to 301-fold in rats and 378-fold in monkeys), peaking at 8-10 days after the first dose. FLT3L-Fc was well tolerated with no adverse findings at doses up to 10 mg/kg administered intravenously twice three weeks apart. In both species, major clinical pathology findings consisted of expansion of white blood cell (WBC) populations including lymphocytes, monocytes, neutrophils, basophils, and large unstained cells, which were pronounced after the first dose. The WBC findings were associated microscopically with histiocytic and mononuclear cell infiltrates in multiple organs. Tissue immunohistochemistry in monkeys showed that the leukocyte infiltrates consisted of hematopoietic progenitor cells and histiocytes with a reactive morphology and were associated with a slight stimulation of regional T and B cell populations. Additional FLT3L-Fc-associated changes included decreases in red blood cell (RBC) mass, increases in RBC distribution width, variable changes in reticulocytes, and transient alterations in platelet counts (rats only). The RBC and WBC findings were associated microscopically with increased hematopoietic cellularity of the bone marrow in both species and increased splenic megakaryocytic extramedullary hematopoiesis in rats. The totality of nonclinical safety data support the clinical development of FLT3L-Fc.
Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Connie Wu, Adeyemi Adedeji, Tanja Zabka, Iraj Hosseini, Radhika Kenkre, Tien Nguyen, Jérémie Decalf, Jennifer Getz, Travis Bainbridge, Christine Moussion, and Gautham Rao are employees of Genentech Inc., a member of the Roche Group, and own stock in the company.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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