Orthogonal interleukin-2 receptor beta (orthoIL-2Rβ)

The Orthogonal interleukin-2 receptor beta (orthoIL-2Rβ) is a synthetic, genetically engineered variant of the human interleukin-2 receptor subunit beta (CD122) [2, 3]. It is designed to function as a selective signaling component in adoptive cell therapies, such as CAR-T or TCR-T cell treatments [4, 6]. By introducing specific mutations into the IL-2 binding interface, the receptor is rendered unresponsive to endogenous wild-type IL-2 but gains high affinity for a complementary engineered IL-2 ligand, such as STK-009 [2, 4]. This orthogonal pair creates a private signaling channel that allows for the precise, dose-dependent expansion and persistence of therapeutic T cells in vivo without stimulating native immune populations like regulatory T cells or natural killer cells [2, 5]. This selectivity aims to minimize the severe systemic toxicities, such as vascular leak syndrome and off-target immune suppression, typically associated with high-dose IL-2 therapy [2, 6]. In clinical development, the orthoIL-2Rβ is often co-expressed with a chimeric antigen receptor to enhance the durability and efficacy of the treatment against various cancers [4, 6].

Other names

Engineered IL-2 receptor betaoIL-2RβhoRbOrthogonal CD122Mutated interleukin-2 receptor subunit beta

The orthogonal IL-2 receptor beta is a mutated version of the CD122 subunit that selectively binds to a matching engineered IL-2 ligand (e.g., STK-009) [2, 4]. This interaction triggers the recruitment of the common gamma chain (CD132), leading to the activation of the JAK-STAT signaling pathway, specifically STAT5 phosphorylation [2, 3]. This private signaling channel promotes the selective expansion, survival, and effector function of engineered T cells (e.g., CAR-T cells) while avoiding the activation of endogenous immune cells and associated systemic toxicities [2, 6].