CTLA-4 / IL-2Rβγ

Class

CD80-IgG4-IL2 variant bispecific fusion protein

Pathway

CTLA-4 blockade + IL-2-driven cytotoxic T-cell/NK-cell activation

This mechanism combines two complementary strategies for stimulating antitumor immunity in a single fusion protein. The first component uses CD80, the natural ligand of the inhibitory receptor CTLA-4, to block CTLA-4 signaling. CTLA-4 is expressed on activated T cells and competes with the co-stimulatory receptor CD28 for CD80/86 binding, dampening the strength of T-cell activation during antigen priming. Neutralizing this interaction removes an early brake on T-cell responses. The second component is an engineered interleukin-2 (IL-2) variant that signals through the IL-2 receptor beta and gamma chains (IL-2Rβγ) found on cytotoxic CD8+ T cells and natural killer (NK) cells, driving their proliferation and cytolytic activity, while avoiding the high-affinity alpha chain (CD25) that natural IL-2 uses to preferentially expand immunosuppressive regulatory T cells. By fusing checkpoint blockade with a lineage-biased cytokine signal into one molecule, the approach aims to simultaneously unleash T-cell priming and directly fuel expansion of the effector cells needed to act on tumors. This dual mechanism is broadly relevant across solid tumor types where checkpoint blockade alone fails to generate sufficient numbers of active effector lymphocytes within the tumor microenvironment.