IL-2 is an enticing immunotherapy because it is a powerful T cell activator. However, as a therapeutic, the lack of selectivity has been a barrier, and its clinical use has been severely limited due to toxicity.
A Differentiated Approach
As recent data has supported a role for IL2Rα in many of IL-2’s liabilities, multiple biopharmaceutical companies initiated development programs recognizing the need for a more selective IL-2, with the hopes to fully realize the potent efficacy of IL-2 while solving its liabilities. Many of these next generation IL-2 programs are categorized as “not alpha” IL-2 variants.
In contrast to our approach, “not alpha” IL-2 variants’ attempts to obtain selectivity are inherently limited, as they rely on differential expression levels of the natural cytokine receptor across different cell types rather than achieving selectivity by design. In clinical studies, these molecules continue to activate multiple cell types, invoke dose-limiting toxicities, and demonstrate monotherapy efficacy lower than that historically achieved by wild-type IL-2 (aldesleukin). Therefore, the therapeutic opportunity to improve upon wild-type IL-2 remains.
