biostudies-literatureTzeng AHHS | NIH | National Cancer InstituteNCI NIH HHS3320-5https://www.ebi.ac.uk/biostudies/studies/S-EPMC4371941biostudies-literatureUnknown112(11)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 Proceedings of the National Academy of Sciences of the United States of AmericaAntigen specificity can be irrelevant to immunocytokine efficacy and biodistribution.PMC4371941CA174795R01 CA174795Kwan BHOpel CFWittrup KDTzeng ANavaratna TfalseAntigen specificity can be irrelevant to immunocytokine efficacy and biodistribution.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 2015-01-01T00:00:00Z2015 Mar2025-06-01T00:13:10.015Z2025-06-01T00:13:10.015ZS-EPMC43719412573385410.1073/pnas.1416159112