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

• Published in: Nature communications 2024-07, Vol.15 (1), p.5842-19, Article 5842
• Main Authors: Malli Cetinbas, Naniye, Monnell, Travis, Soomer-James, Jahna, Shaw, Pamela, Lancaster, Kelly, Catcott, Kalli C., Dolan, Melissa, Mosher, Rebecca, Routhier, Caitlin, Chin, Chen-Ni, Toader, Dorin, Duvall, Jeremy, Bukhalid, Raghida, Lowinger, Timothy B., Damelin, Marc
• Format: Article
• Language: English
• Subjects: 13/106; 13/21; 13/31; 14/1; 14/35; 38/39; 38/88; 38/90; 631/250/262; 631/67/1059/2325; 631/67/580; 82/1; 82/51; Agonists; Animal models; Animals; Antibodies; Anticancer properties; Antitumor agents; Cancer; Cancer immunotherapy; Cell activation; Cell culture; Cell Line, Tumor; Chemokines; Conjugates; Cytokines; Cytokines - metabolism; Female; Humanities and Social Sciences; Humans; Immune response; Immunity, Innate - drug effects; Immunoconjugates - administration & dosage; Immunoconjugates - pharmacology; Immunotherapy; Immunotherapy - methods; Innate immunity; Interferon; Interferon Lambda; Interferon Type I - immunology; Interferons - metabolism; Membrane Proteins - agonists; Membrane Proteins - immunology; Mice; Mice, Inbred C57BL; multidisciplinary; Myeloid cells; Myeloid Cells - drug effects; Myeloid Cells - immunology; Neoplasms - drug therapy; Neoplasms - immunology; Receptors, IgG - agonists; Receptors, IgG - immunology; Receptors, IgG - metabolism; Science; Science (multidisciplinary); Tumor cells; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49932-4

Activating 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. Activation of the STING pathway can promote anti-tumor immunity. Here the authors generate tumor cell-directed STING agonist antibody-drug conjugates that activate STING in tumor and myeloid cells, promoting anti-tumor innate immune responses in preclinical cancer models.