Tumor cell-directed STING agonist antibody-drug conjugates induce type III interferons and anti-tumor innate immune responses

• DOI: 10.1038/s41467-024-49932-4
• Publication Date: 2024-07-11T19:02:16Z
• Authors: Naniye Malli Ceti...; Travis Monnell; Jahna Soomer-James; Pamela Shaw; Kelly Lancaster; Kalli C. Catcott; Melissa Dolan; Rebecca Mosher; Caitlin Routhier; Chen-Ni Chin; Dorin Toader; Jeremy Duvall; Raghida Bukhalid; Timothy B. Lowinger; Marc Damelin
• Keywords: 0301 basic medicine; Immunoconjugates; Science; Q; Receptors, IgG; Membrane Proteins; Article; Immunity, Innate; Interferon Lambda; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Cell Line, Tumor; Neoplasms; Interferon Type I; Animals; Humans; Cytokines; Female; Myeloid Cells; Interferons; Immunotherapy

AbstractActivating interferon responses with STING agonists (STINGa) is a current cancer immunotherapy strategy, and therapeutic modalities that enable tumor-targeted delivery via systemic administration could be beneficial. Here we demonstrate that tumor cell-directed STING agonist antibody-drug-conjugates (STINGa ADCs) activate STING in tumor cells and myeloid cells and induce anti-tumor innate immune responses in in vitro, in vivo (in female mice), and ex vivo tumor models. We show that the tumor cell-directed STINGa ADCs are internalized into myeloid cells by Fcγ-receptor-I in a tumor antigen-dependent manner. Systemic administration of STINGa ADCs in mice leads to STING activation in tumors, with increased anti-tumor activity and reduced serum cytokine elevations compared to a free STING agonist. Furthermore, STINGa ADCs induce type III interferons, which contribute to the anti-tumor activity by upregulating type I interferon and other key chemokines/cytokines. These findings reveal an important role for type III interferons in the anti-tumor activity elicited by STING agonism and provide rationale for the clinical development of tumor cell-directed STINGa ADCs.