Engineered orthogonal interleukin-2 receptor subunit beta (ortho-IL-2Rβ) (ortho-IL-2Rβ)

The engineered orthogonal interleukin-2 receptor subunit beta (ortho-IL-2Rβ) is a synthetically modified version of the human CD122 protein, specifically engineered to interact with a complementary orthogonal interleukin-2 (ortho-IL-2) ligand. This receptor-ligand pair is designed to be "orthogonal" to the natural IL-2 system, meaning the engineered receptor does not respond to endogenous IL-2, and the engineered ligand does not bind to the wild-type IL-2 receptors found on native immune cells (Sockolosky et al., Science, 2018). In the context of SYNCAR-001, a CD19-directed CAR-T cell therapy, the ortho-IL-2Rβ is expressed on the surface of the CAR-T cells to provide a dedicated signaling channel for growth and activation (Synthekine, 2023). The primary therapeutic application of this target is to allow for the controlled expansion and maintenance of CAR-T cells in vivo through the administration of the orthogonal ligand STK-009 (ClinicalTrials.gov, NCT05612035). By bypassing the wild-type IL-2 receptor, this technology avoids the systemic toxicities typically associated with high-dose IL-2 therapy, such as vascular leak syndrome, and prevents the unintended stimulation of regulatory T cells (Tregs) that could suppress the anti-tumor immune response. This system represents a significant advancement in adoptive cell therapy, offering a mechanism to enhance the persistence and potency of CAR-T cells in patients with B-cell malignancies while maintaining a favorable safety profile.

Other names

Orthogonal IL-2 receptor betaOrthogonal CD122STK-009 receptorEngineered CD122

Selective activation of the JAK/STAT signaling pathway in engineered cells upon binding of an orthogonal ligand (STK-009) (Sockolosky et al., Science, 2018).