Novel IL13RA2-targeted immunocytokines exhibit superior antitumor activities

Th1-type cytokines such as interleukin-2 (IL-2) and interleukin-12 (IL-12) are known for their potent antitumor activities, but their clinical application has been hindered by significant side effects. Immunocytokines (ICs) that combine cytokines with antibodies have shown favorable therapeutic and safety outcomes in clinical trials. In this study we first investigated the expression patterns and prognostic significance of IL13RA2 across various cancer types through a comprehensive analysis of the TIMER2 and TCGA datasets. Subsequently, we generated 52B8, a neutralizing antibody against interleukin-13 receptor alpha 2 (IL13RA2) as well as three ICs incorporating interleukin-2 (IL-2), interleukin-12 (IL-12), or both, designed as 52B8-IL2, 52B8-IL12 and 52B8-IL2/12, respectively. The ICs exhibited potent and dose-dependent anticancer activity both in vitro and in MC38-hIL13RA2-GFP and A375 tumor xenograft models in vivo. In addition, they exhibited significantly reduced side effects through targeted cytokine delivery as well as enhanced immune cell infiltration into tumors. Collectively, our results suggest that IL13RA2-targeting ICs represent a promising therapeutic strategy for the treatment of IL13RA2-positive tumors.