Interleukin-2 (IL-2) is a cytokine critical for immune regulation, primarily produced by activated T cells. It promotes the proliferation and differentiation of T cells, natural killer (NK) cells, and regulatory T cells (Tregs), balancing immune activation and tolerance. IL-2 exerts its effects by binding to heterotrimeric receptors composed of α (CD25), β (CD122), and γ (CD132) chains. The high-affinity receptor (αβγ) is expressed on Tregs and activated T cells, while intermediate-affinity receptors (βγ) are found on NK cells and memory T cells.
IL-2-targeting antibodies have emerged as therapeutic tools to modulate immune responses. Agonistic antibodies, such as those targeting the βγ receptor subunits, aim to boost anti-tumor immunity by selectively activating effector T cells and NK cells, bypassing Treg stimulation. Conversely, antagonistic antibodies, like those blocking CD25. inhibit IL-2 signaling to suppress overactive immune responses in autoimmune diseases or transplant rejection.
Clinical development has faced challenges, including toxicity from systemic immune activation and the pleiotropic nature of IL-2 signaling. To address this, engineered IL-2 variants and antibody-cytokine fusion proteins (e.g., immunocytokines) have been designed to improve specificity, prolong half-life, or reduce off-target effects. For example, "not-alpha" IL-2 analogs preferentially bind βγ receptors, enhancing anti-cancer activity while minimizing Treg expansion.
IL-2 antibodies continue to be explored in cancer immunotherapy, autoimmune disorders, and infectious diseases, reflecting their dual role in amplifying or dampening immunity based on therapeutic context.