Enhanced antitumor immune responses via a new agent [131I]-labeled dual-target immunosuppressant
Chunjuan Jiang, Qiwei Tian, Xiaoping Xu, Panli Li, Simin He, Jian Chen, Bolin Yao, Jianping Zhang, Ziyi Yang, Shaoli Song
Abstract
Abstract Radionuclides theranostic are ideal “partners” for bispecific antibodies to explore the immune response of patients and synergistic treatment. A bispecific single-domain antibody-Fc fusion protein, KN046, exhibits a good treatment effect by binding to programmed cell death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). An ionizing-radiation stimulus mediated by a low-dose of [ 131 I] may be used for immunopotentiation. In this study, we established [ 131 I]-labeled KN046 as a novel radioimmunotherapy agent to treat malignant melanoma and explored the mechanism. Methods After intravenous injection of [ 131 I]-KN046, SPECT/CT imaging was applied to identify candidate targets for KN046 immunotherapy. [ 18 F]-FDG and [ 68 Ga]-NOTA-GZP (granzyme B-specific PET imaging agent) micro-PET/CT imaging was used to assess the immune response in vivo after [ 131 I]-KN046 treatment. The synergistic treatment effect of [ 131 I]-KN046 was evaluated by exploring the [ 131 I]-based radionuclide-induced release of tumor immunogenicity-related antigens as well as the histology and survival of tumor-bearing mice after treatment. Results The constructed [ 131 I]-KN046 exhibited high affinity and specificity for PD-L1/CTLA-4 immune targets and had excellent in vivo intratumoral retention capability so as to achieve good antitumor efficacy. More importantly, the combination of low-dose [ 131 I] and KN046-enhanced immunosensitivity increased the immunotherapy response rates significantly. Exposure of tumor cells to [ 131 I]-KN046 led to upregulated expression of MHC-I and Fas surface molecules and significant increases in the degree of T-cell activation and counts of tumor-infiltrating immunocytes. Conclusion Use of low-dose [ 131 I] combined with a dual-target immunosuppressant could be exploited to identify the subset of treatment responders but also exhibited great potential for enhancing antitumor immune responses.