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

Naniye Malli Cetinbas (), 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 and Marc Damelin ()
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Naniye Malli Cetinbas: Mersana Therapeutics Inc. Cambridge MA
Travis Monnell: Mersana Therapeutics Inc. Cambridge MA
Jahna Soomer-James: Mersana Therapeutics Inc. Cambridge MA
Pamela Shaw: Mersana Therapeutics Inc. Cambridge MA
Kelly Lancaster: Mersana Therapeutics Inc. Cambridge MA
Kalli C. Catcott: Mersana Therapeutics Inc. Cambridge MA
Melissa Dolan: Mersana Therapeutics Inc. Cambridge MA
Rebecca Mosher: Mersana Therapeutics Inc. Cambridge MA
Caitlin Routhier: Mersana Therapeutics Inc. Cambridge MA
Chen-Ni Chin: Mersana Therapeutics Inc. Cambridge MA
Dorin Toader: Mersana Therapeutics Inc. Cambridge MA
Jeremy Duvall: Mersana Therapeutics Inc. Cambridge MA
Raghida Bukhalid: Mersana Therapeutics Inc. Cambridge MA
Timothy B. Lowinger: Mersana Therapeutics Inc. Cambridge MA
Marc Damelin: Mersana Therapeutics Inc. Cambridge MA

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49932-4

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