NKTR-358: A novel regulatory T-cell stimulator that selectively stimulates expansion and suppressive function of regulatory T cells for the treatment of autoimmune and inflammatory diseases.

Autor:	Dixit N; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Fanton C; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Langowski JL; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Kirksey Y; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Kirk P; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Chang T; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Cetz J; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Dixit V; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Kim G; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Kuo P; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Maiti M; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Tang Y; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., VanderVeen LA; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Zhang P; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Lee M; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Ritz J; Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA., Kamihara Y; Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA., Ji C; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Rubas W; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Sweeney TD; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Doberstein SK; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA., Zalevsky J; Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA.
Jazyk:	angličtina
Zdroj:	Journal of translational autoimmunity [J Transl Autoimmun] 2021 May 06; Vol. 4, pp. 100103. Date of Electronic Publication: 2021 May 06 (Print Publication: 2021).
DOI:	10.1016/j.jtauto.2021.100103
Abstrakt:	Impaired interleukin-2 (IL-2) production and regulatory T-cell dysfunction have been implicated as immunological mechanisms central to the pathogenesis of multiple autoimmune and inflammatory diseases. NKTR-358, a novel regulatory T-cell stimulator, is an investigational therapeutic that selectively restores regulatory T-cell homeostasis in these diseases. We investigated NKTR-358's selectivity for regulatory T-cells, receptor-binding properties, ex vi vo and in vivo pharmacodynamics, ability to suppress conventional T-cell proliferation in mice and non-human primates, and functional activity in a murine model of systemic lupus erythematosus. In vitro, NKTR-358 demonstrated decreased affinity for IL-2Rα, IL-2Rβ, and IL-2Rαβ compared with recombinant human IL-2 (rhIL-2). A single dose of NKTR-358 in cynomolgus monkeys produced a greater than 15-fold increase in regulatory T-cells, and the increase lasted until day 14, while daily rhIL-2 administration for 5 days only elicited a 3-fold increase, which lasted until day 7. Repeated dosing of NKTR-358 over 6 months in cynomolgus monkeys elicited cyclical, robust increases in regulatory T-cells with no loss in drug activity over the course of treatment. Regulatory T-cells isolated from NKTR-358-treated mice displayed a sustained, higher suppression of conventional T-cell proliferation than regulatory T-cells isolated from vehicle-treated mice. NKTR-358 treatment in a mouse model (MRL/MpJ-Fas lpr ) of systemic lupus erythematosus for 12 weeks maintained elevated regulatory T-cells for the treatment duration and ameliorated disease progression. Together, these results suggest that NKTR-358 has the ability to elicit sustained and preferential proliferation and activation of regulatory T-cells without corresponding effects on conventional T-cells, with improved pharmacokinetics compared with rhIL-2. Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. All authors, except JR and YK, were employees and shareholders of Nektar Therapeutics during this study. JR reports research funding from Amgen, Equillium, and Kite Pharma and consulting income from Aleta Biotherapeutics, Avrobio, Celgene, Falcon Therapeutics, LifeVault Bio, Rheos Medicines, Tal, and TScan Therapeutics. YK has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (© 2021 The Authors.)
Databáze:	MEDLINE
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