期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：11
页码：3320-3325
DOI：10.1073/pnas.1416159112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceCytokines (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. Cytokine therapy can activate potent, sustained antitumor responses, but collateral toxicity often limits dosages. Although antibody-cytokine fusions (immunocytokines) have been designed with the intent to localize cytokine activity, systemic dose-limiting side effects are not fully ameliorated by attempted tumor targeting. Using the s.c. B16F10 melanoma model, we found that a nontoxic dose of IL-2 immunocytokine synergized with tumor-specific antibody to significantly enhance therapeutic outcomes compared with immunocytokine monotherapy, concomitant with increased tumor saturation and intratumoral cytokine responses. Examination of cell subset biodistribution showed that the immunocytokine associated mainly with IL-2R-expressing innate immune cells, with more bound immunocytokine present in systemic organs than the tumor microenvironment. More surprisingly, immunocytokine antigen specificity and Fc{gamma} receptor interactions did not seem necessary for therapeutic efficacy or biodistribution patterns because immunocytokines with irrelevant specificity and/or inactive mutant Fc domains behaved similarly to tumor-specific immunocytokine. IL-2-IL-2R interactions, rather than antibody-antigen targeting, dictated immunocytokine localization; however, the lack of tumor targeting did not preclude successful antibody combination therapy. Mathematical modeling revealed immunocytokine size as another driver of antigen targeting efficiency. This work presents a safe, straightforward strategy for augmenting immunocytokine efficacy by supplementary antibody dosing and explores underappreciated factors that can subvert efforts to purposefully alter cytokine biodistribution.
