Human and murine IL2 receptors differentially respond to the human-IL2 component of immunocytokines

摘要

The humanized immunocytokine, hu14.18-IL2 (ICp), leads to the immune cell-mediated destruction of GD2-expressing tumors in mouse models, resulting in potent antitumor effects with negligible IL2-related toxicity. In contrast, when ICp is used clinically, antitumor activity is accompanied by dose-limiting IL2-related toxicities. These species-specific differences in ICp toxicity may be linked to differential binding to mouse vs. human IL2 receptors (IL2Rs). We evaluated immunocytokines genetically engineered to preferentially bind either high-affinity αβγ-IL2Rs or intermediate-affinity βγ-IL2Rs. These ICs have the IL2 fused to the C-terminus of the IgG light chains rather than the heavy chains. We found that IC35, containing intact hulL2, maintained activation of human and mouse αβγ-IL2Rs but exhibited a 20-fold reduction in the ability to stimulate human βγ-IL2Rs, with no activation of mouse βγ-IL2Rs at the concentrations tested. The reduced ability of IC35 to stimulate human βγ-IL2Rs (associated with IL2-toxicities) makes it a potential candidate for clinical trials where higher clinical IC doses might enable better tumor targeting and increased antitumor effects with less toxicity. Contrastingly, ICSK (IC with an IL2 mutein that has enhanced binding to the IL2R β-chain) showed increased activation over ICp on mouse βγ-IL2Rs, with a dose-response curve similar to that seen with IC35 on human βγ-IL2Rs. Our data suggest that ICSK might be used in mouse models to simulate the anticipated effects of IC35 in clinical testing. Understanding the differences in species-dependent IL2R activation should facilitate the design of reagents and mouse models that better simulate the potential activity of IL2-based immunotherapy in patients.