4.5 Article

Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity

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NATURE CANCER
卷 2, 期 1, 页码 18-+

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NATURE PORTFOLIO
DOI: 10.1038/s43018-020-00136-x

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  1. Stanford BioX Bowes Fellowship
  2. EMBO Long-Term Fellowship [ALTF 1141-2017]
  3. Swiss National Science Foundation Early Postdoc Mobility Fellowship [P2ZHP3-171741]
  4. National Institutes of Health (NIH)/National Institute and General Medical Sciences Cell and Molecular Biology Training [T32GM007276]
  5. NIH [CA209971, CA222969, 1DP2OD022550-01]
  6. Swiss National Science Foundation (SNF) [P2ZHP3_171741] Funding Source: Swiss National Science Foundation (SNF)

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Alonso and colleagues have developed immune-stimulating antibody conjugates that can specifically deliver TLR7/8 agonists to tumors, inducing durable antitumor immunity.
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, Fc gamma-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.

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