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bioRxiv · 10.1101/862789

Regulatory T cell expansion by a highly CD25-dependent IL-2 mutein arrests ongoing autoimmunity

Khoryati, L.·Pham, M. N.·Sherve, M.·Kumari, S.·Cook, K.·Pearson, J.·Bogdani, M.·Campbell, D. J.·Gavin, M. A.
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Abstract

Interleukin-2 (IL-2) controls the homeostasis and function of regulatory T cells (Tregs) 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 Treg-specificity. From a panel of rationally designed IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced Treg-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 Treg enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall Treg growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared to Fc-fused wild-type IL-2. Preferential Treg enrichment was also observed in the presence of activated pathogenic T cells in the autoimmune target organ, despite a loss of Treg-selectivity in an IL-2R-proximal response. These features allowed for extended resolution of spontaneous autoimmunity using infrequent dosing schedules. Thus, IL-2 muteins enable efficient, flexible, and targeted control of the autoimmune response. One Sentence SummaryA CD25-dependent IL-2 mutein selectively expands regulatory T cells and provides potent and targeted control of autoimmunity.

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Khoryati, L., Pham, M. N., Sherve, M., Kumari, S., Cook, K., Pearson, J., Bogdani, M., Campbell, D. J., Gavin, M. A.. 2019-12-03. Regulatory T cell expansion by a highly CD25-dependent IL-2 mutein arrests ongoing autoimmunity. https://doi.org/10.1101/862789

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