An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice.

Autor: Khoryati L; Immunology Research Program, Benaroya Research Institute, Seattle, WA 98101, USA., Pham MN; Immunology Research Program, Benaroya Research Institute, Seattle, WA 98101, USA., Sherve M; Immunology Research Program, Benaroya Research Institute, Seattle, WA 98101, USA., Kumari S; Immunology Research Program, Benaroya Research Institute, Seattle, WA 98101, USA., Cook K; Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, CA 94080, USA., Pearson J; Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, CA 94080, USA., Bogdani M; Matrix Biology Program, Benaroya Research Institute, Seattle, WA 98101, USA., Campbell DJ; Immunology Research Program, Benaroya Research Institute, Seattle, WA 98101, USA. campbell@benaroyaresearch.org mgavin@omeros.com.; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA., Gavin MA; Immunology Research Program, Benaroya Research Institute, Seattle, WA 98101, USA. campbell@benaroyaresearch.org mgavin@omeros.com.
Jazyk: angličtina
Zdroj: Science immunology [Sci Immunol] 2020 Aug 14; Vol. 5 (50).
DOI: 10.1126/sciimmunol.aba5264
Abstrakt: Interleukin-2 (IL-2) controls the homeostasis and function of regulatory T (T reg ) cells, and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2-based therapeutics with improved T reg cell specificity. From a panel of rationally designed murine IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced T reg cell selectivity due to increased dependence on the IL-2 receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective T reg cell enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall T reg cell growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared with Fc-fused wild-type IL-2. Preferential T reg cell enrichment was also observed in the presence of activated pathogenic T cells in the pancreas of nonobese diabetic (NOD) mice, despite a loss of T reg cell selectivity in an IL-2R proximal response. These properties facilitated potent and extended resolution of NOD diabetes with infrequent dosing schedules.
(Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze: MEDLINE
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