Engineered orthogonal interleukin-2 receptor beta chain (Ortho-IL-2Rβ)

The **engineered orthogonal interleukin-2 receptor beta chain** is a genetically modified version of the human (or murine) IL-2 receptor beta subunit, altered at key residues to **abolish binding to native IL-2 while selectively binding an engineered "orthogonal" IL-2 cytokine**. This creates a synthetic, highly specific "lock-and-key" system wherein only T cells expressing the engineered receptor respond to the administered orthogonal cytokine. The strategy enables **selective in vivo expansion and activation of these engineered (e.g., CAR-modified) T cells**, while sparing native (wild-type) immune cells and reducing the systemic toxicities associated with wild-type IL-2 therapy. This has been shown to dramatically increase the therapeutic index and anti-tumor efficacy of adoptive T cell therapies in preclinical models and is under clinical investigation.

Other names

Ortho-IL-2Rβorthogonal IL-2Rβortho-hIL-2Rβmutant IL-2 receptor betaengineered IL-2 receptor beta

Orthogonal cytokine binds mutant (engineered) IL-2 receptor beta → triggers JAK-STAT and MAPK signaling only in cells expressing the engineered receptor, enabling selective proliferation/activation of therapeutic cells, with minimal effect on endogenous cells