Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution

Significance Cytokines (potent immunostimulatory proteins) exert powerful antitumor effects but often cause severe whole-body inflammation when used as cancer therapies. Contrary to the current paradigm that fusion to antitumor antibodies can constrain cytokine activity to tumors, we have found that, for some immunocytokines incorporating the cytokine IL-2, the cytokine moiety overrides antibody-mediated targeting, localizing the fusion protein to IL-2 receptor-expressing cells rather than tumor cells. Although the IL-2 immunocytokines did not selectively home to tumors, they persisted longer in circulation than free IL-2, such that a nontoxic immunocytokine dose could synergize with tumor-specific antibody to cure mice with aggressive solid tumors.