Interleukin-2 receptor subunit beta and gamma on programmed cell death protein 1-positive cells (IL-2Rβγ/PD-1+)

The Interleukin-2 receptor beta-gamma (IL-2Rβγ) complex on PD-1-positive cells is a specialized therapeutic target designed to enhance anti-tumor immunity while minimizing the systemic toxicity typically associated with wild-type IL-2 therapy. The IL-2Rβγ heterodimer, composed of the CD122 and CD132 subunits, serves as the intermediate-affinity receptor for IL-2 and is primarily expressed on effector CD8+ T cells and Natural Killer (NK) cells (UniProt P14784, P31785). By specifically targeting this receptor complex on cells that also express Programmed cell death protein 1 (PD-1), therapies can selectively deliver IL-2 signaling to 'exhausted' or tumor-reactive T cells within the tumor microenvironment (Cancer Cell, 2022). This dual-targeting approach is engineered to bypass the activation of regulatory T cells (Tregs), which express the high-affinity IL-2Rα (CD25) subunit and can suppress the anti-tumor immune response. Drugs such as RO7284755 (PD1-IL2v) utilize this mechanism to promote the proliferation and cytotoxic activity of tumor-infiltrating lymphocytes without the broad systemic activation that leads to vascular leak syndrome (Roche, 2021). Consequently, this target represents a significant advancement in the development of next-generation immunotherapies for various solid tumors.

Other names

PD-1-targeted IL-2 receptorIL-2Rβγ on PD-1+ cellsCD122/CD132 on PD-1+ T cellsPD1-IL2v targetIntermediate-affinity IL-2 receptor on PD-1+ cells

Selective agonism of the intermediate-affinity IL-2 receptor (IL-2Rβγ) specifically on PD-1-expressing effector T and NK cells. This is achieved using a modified IL-2 variant (IL2v) that lacks binding to the high-affinity IL-2Rα (CD25) subunit, thereby avoiding the activation of regulatory T cells and reducing systemic toxicity while concentrating the immune-stimulatory signal on exhausted tumor-infiltrating lymphocytes (PubMed: 35143758, Roche Pipeline).