TLR2 agonism reverses chemotherapy-induced neutropenia in Macaca fascicularis .

Autor: Laping NJ; New Targets Incubator and., DeMartino MP; New Targets Incubator and., Cottom JE; PTS-Biological Sciences, GlaxoSmithKline, King of Prussia, PA., Axten JM; New Targets Incubator and., Emery JG; New Targets Incubator and., Guss JH; PTS-Biological Sciences, GlaxoSmithKline, King of Prussia, PA., Burman M; PTS-Biological Sciences, GlaxoSmithKline, King of Prussia, PA., Foley JJ; PTS-Biological Sciences, GlaxoSmithKline, King of Prussia, PA., Cheung M; New Targets Incubator and., Oliff A; New Targets Incubator and., Kumar S; New Targets Incubator and.
Jazyk: angličtina
Zdroj: Blood advances [Blood Adv] 2017 Dec 08; Vol. 1 (26), pp. 2553-2562. Date of Electronic Publication: 2017 Dec 08 (Print Publication: 2017).
DOI: 10.1182/bloodadvances.2017010611
Abstrakt: Neutropenia is a common consequence of radiation and chemotherapy in cancer patients. The resulting immunocompromised patients become highly susceptible to potentially life-threatening infections. Granulocyte colony-stimulating factor (G-CSF) is known to stimulate neutrophil production and is widely used as a treatment of chemotherapy-induced neutropenia. A small-molecule G-CSF secretagogue without a requirement for refrigerated supply chain would offer a more convenient and cost-effective treatment of chemotherapy-induced neutropenia. Bacterial lipopeptides activate innate immune responses through Toll-like receptor 2 (TLR2) and induce the release of cytokines, including G-CSF, from macrophages, monocytes, and endothelial. Pam 2 CSK 4 is a synthetic lipopeptide that effectively mimics bacterial lipoproteins known to activate TLR2 receptor signaling through the TLR2/6 heterodimer. Substrate-based drug design led to the discovery of GSK3277329, which stimulated the release of G-CSF in activated THP-1 cells, peripheral blood mononuclear cells, and human umbilical vein endothelial cells. When administered subcutaneously to cynomolgus monkeys ( Macaca fasciculari s), GSK3277329 caused systemic elevation of G-CSF and interleukin-6 (IL-6), but not IL-1β or tumor necrosis factor α, indicating a selective cytokine-stimulation profile. Repeat daily injections of GSK3277329 in healthy monkeys also raised circulating neutrophils above the normal range over a 1-week treatment period. More importantly, repeated daily injections of GSK3277329 over a 2-week period restored neutrophil loss in monkeys given chemotherapy treatment (cyclophosphamide, Cytoxan). These data demonstrate preclinical in vivo proof of concept that TLR2 agonism can drive both G-CSF induction and subsequent neutrophil elevation in the cynomolgus monkey and could be a therapeutic strategy for the treatment of chemotherapy-induced neutropenia.
Competing Interests: Conflict-of-interest disclosure: The authors are employees of GlaxoSmithKline PLC.
Databáze: MEDLINE
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