| Literature DB >> 35121890 |
Shelley E Ackerman1,2, Cecelia I Pearson2, Joshua D Gregorio2, Joseph C Gonzalez2, Justin A Kenkel2,3, Felix J Hartmann3, Angela Luo2, Po Y Ho2, Heidi LeBlanc2, Lisa K Blum2, Samuel C Kimmey3,4, Andrew Luo2, Murray L Nguyen2, Jason C Paik3, Lauren Y Sheu3, Benjamin Ackerman5, Arthur Lee2, Hai Li2, Jennifer Melrose2, Richard P Laura2, Vishnu C Ramani2, Karla A Henning2, David Y Jackson2, Brian S Safina2, Grant Yonehiro2, Bruce H Devens2, Yaron Carmi3,6, Steven J Chapin2, Sean C Bendall3, Marcin Kowanetz2, David Dornan2, Edgar G Engleman3, Michael N Alonso7,8.
Abstract
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.Entities:
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Year: 2020 PMID： 35121890 PMCID： PMC9012298 DOI： 10.1038/s43018-020-00136-x
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347