Enhanced antitumor immune responses via a new agent [¹³¹I]-labeled dual-target immunosuppressant.

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 [¹³¹I] may be used for immunopotentiation. In this study, we established [¹³¹I]-labeled KN046 as a novel radioimmunotherapy agent to treat malignant melanoma and explored the mechanism. After intravenous injection of [¹³¹I]-KN046, SPECT/CT imaging was applied to identify candidate targets for KN046 immunotherapy. [¹⁸F]-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 [¹³¹I]-KN046 treatment. The synergistic treatment effect of [¹³¹I]-KN046 was evaluated by exploring the [¹³¹I]-based radionuclide-induced release of tumor immunogenicity-related antigens as well as the histology and survival of tumor-bearing mice after treatment. The constructed [¹³¹I]-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 [¹³¹I] and KN046-enhanced immunosensitivity increased the immunotherapy response rates significantly. Exposure of tumor cells to [¹³¹I]-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. Use of low-dose [¹³¹I] 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.