Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps.
Research paper by
Suman S Mitra, Aaron M AM Ring, Shoba S Amarnath, Jamie B JB Spangler, Peng P Li, Wei W Ju, Suzanne S Fischer, Jangsuk J Oh, Rosanne R Spolski, Kipp K Weiskopf, Holbrook H Kohrt, Jason E JE Foley, Sumati S Rajagopalan, Eric O EO Long, Daniel H DH Fowler, Thomas A TA Waldmann, K Christopher KC Garcia, Warren J WJ Leonard
Interleukin-2 (IL-2) regulates lymphocyte function by signaling through heterodimerization of the IL-2Rβ and γc receptor subunits. IL-2 is of considerable therapeutic interest, but harnessing its actions in a controllable manner remains a challenge. Previously, we have engineered an IL-2 "superkine" with enhanced affinity for IL-2Rβ. Here, we describe next-generation IL-2 variants that function as "receptor signaling clamps." They retained high affinity for IL-2Rβ, inhibiting binding of endogenous IL-2, but their interaction with γc was weakened, attenuating IL-2Rβ-γc heterodimerization. These IL-2 analogs acted as partial agonists and differentially affected lymphocytes poised at distinct activation thresholds. Moreover, one variant, H9-RETR, antagonized IL-2 and IL-15 better than blocking antibodies against IL-2Rα or IL-2Rβ. Furthermore, this mutein prolonged survival in a model of graft-versus-host disease and blocked spontaneous proliferation of smoldering adult T cell leukemia (ATL) T cells. This receptor-clamping approach might be a general mechanism-based strategy for engineering cytokine partial agonists for therapeutic immunomodulation.