Engineered orthogonal interleukin-2 receptor beta subunit (orthoIL-2Rβ)

Engineered orthogonal interleukin-2 receptor beta subunit (orthoIL-2Rβ) refers to a mutated version of the IL-2 receptor beta chain, altered at specific amino acids (e.g., H134D, Y135F in murine, analogous changes in human) to abolish binding with wild-type IL-2, while retaining high-affinity binding with a cognate, engineered version of IL-2 ("orthogonal" IL-2 or STK-009). This orthogonal cytokine-receptor pair enables precise and selective activation and expansion of engineered T cells (such as CAR-T cells) that express orthoIL-2Rβ, with minimal stimulation of endogenous, non-engineered immune cells. This technology is poised to improve safety and efficacy in cellular immunotherapies, particularly for cancer, by reducing systemic cytokine toxicity and increasing therapeutic cell persistence and antitumor function.

Other names

Orthogonal IL-2 receptor beta subunitOrthoIL-2RβOrtho-hIL-2Rβ (for the human version)hoRβ (in some datasets and presentations, for "human orthogonal Rβ")

Selective activation: Only lymphocytes expressing the engineered orthogonal IL-2Rβ are stimulated by the corresponding orthogonal IL-2 mutein, enabling highly specific expansion of these engineered cells while avoiding broad activation of native immune populations. JAK/STAT5 pathway activation (same downstream signaling as native IL-2Rβ). Used as a "lock and key" system in cell therapy to tightly control therapeutic T cell populations in vivo.