期刊
JOURNAL OF IMMUNOTHERAPY
卷 32, 期 9, 页码 887-894出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CJI.0b013e3181b528da
关键词
interleukin-2; regulatory T cells; antagonist engineering; cytokine engineering
资金
- NIAID NIH HHS [R01 AI065824] Funding Source: Medline
The immunosuppressive effects of CD4(+) CD25 high regulatory T cells (Tregs) interfere with antitumor immune responses in cancer patients. Here, we present a novel class of engineered human interleukin (IL)-2 analogs that antagonizes the IL-2 receptor, for inhibiting regulatory T cell suppression. These antagonists have been engineered for high affinity to the alpha subunit of the IL-2 receptor and very low affinity to either the beta or gamma subunit, resulting in a signaling-deficient IL-2 analog that sequesters the IL-2 receptor alpha subunit from wild type IL-2. Two variants V91R and Q126T with residue substitutions that disrupt the beta and gamma subunit bindings interfaces, respectively, have been characterized in both a T cell line and in human primary Tregs. These mutants retain their high affinity bonding to IL-2 receptor alpha subunit but to not activate STAT5 phosphorylation or stimulate T cell growth. The 2 mutants competitively antagonize wild-type IL-2 signaling through the IL-2 receptor with similar efficacy, with inhibition constants of 183 pM for V91R and 216 pM for Q126T. Here, we present a novel approach to CD25-mediated Treg inhibition, with the use of an engineered human IL-2 analog that antagonizes the IL-2 receptor.
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