Immune-stimulating antibody conjugates elicit robust myeloid activation and durable anti-tumor immunity
| Autor: | Hai Li, Andrew Luo, Steven J. Chapin, Shelley Erin Ackerman, Marcin Kowanetz, Michael N. Alonso, Po Y. Ho, Arthur Lee, Karla Henning, Samuel C. Kimmey, Benjamin Ackerman, Joshua D. Gregorio, Brian Safina, Vishnu C. Ramani, David Dornan, Lauren Y. Sheu, Jennifer Melrose, Cecelia Pearson, Richard P. Laura, Bruce H. Devens, Justin A. Kenkel, Edgar G. Engleman, Lisa Blum, David Y. Jackson, Heidi N. Leblanc, Joseph C. Gonzalez, Grant Yonehiro, Yaron Carmi, Felix J. Hartmann, Sean C. Bendall, Murray L. Nguyen, Angela Luo, Jason C. Paik |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Myeloid Adaptive Immunity Article Mice Immune system Antigens Neoplasm Neoplasms Tumor Microenvironment Medicine Animals Humans Tumor microenvironment biology business.industry Pattern recognition receptor TLR7 Tumor antigen medicine.anatomical_structure Oncology Systemic administration Cancer research biology.protein ST Elevation Myocardial Infarction Immunotherapy Antibody business |
| Zdroj: | Nat Cancer |
| Popis: | Innate pattern recognition receptor agonists, including Toll-like receptors (TLRs), alter the tumor microenvironment and prime adaptive antitumor immunity. However, TLR agonists present toxicities associated with widespread immune activation after systemic administration. To design a TLR-based therapeutic suitable for systemic delivery and capable of safely eliciting tumor-targeted responses, we developed immune-stimulating antibody conjugates (ISACs) comprising a TLR7/8 dual agonist conjugated to tumor-targeting antibodies. Systemically administered human epidermal growth factor receptor 2 (HER2)-targeted ISACs were well tolerated and triggered a localized immune response in the tumor microenvironment that resulted in tumor clearance and immunological memory. Mechanistically, ISACs required tumor antigen recognition, Fcγ-receptor-dependent phagocytosis and TLR-mediated activation to drive tumor killing by myeloid cells and subsequent T-cell-mediated antitumor immunity. ISAC-mediated immunological memory was not limited to the HER2 ISAC target antigen since ISAC-treated mice were protected from rechallenge with the HER2− parental tumor. These results provide a strong rationale for the clinical development of ISACs. Alonso and colleagues develop immune-stimulating antibody conjugates capable of specific delivery of TLR7/8 agonists to tumors, which induces durable antitumor immunity. |
| Databáze: | OpenAIRE |
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