Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution
Author(s)Tzeng, Alice; Navaratna, Tejas; Kwan, Byron Hua; Opel, Cary Francis; Wittrup, Karl Dane
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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 Fcγ 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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Chemical Engineering
Proceedings of the National Academy of Sciences
National Academy of Sciences (U.S.)
Tzeng, Alice, Byron H. Kwan, Cary F. Opel, Tejas Navaratna, and K. Dane Wittrup. “Antigen Specificity Can Be Irrelevant to Immunocytokine Efficacy and Biodistribution.” Proc Natl Acad Sci USA 112, no. 11 (March 2, 2015): 3320–3325.
Final published version