To develop a safe TLR-activated, tumor-targeted therapeutic, Ackerman et al. designed Immune-Stimulating Antibody Conjugates (ISACs), by conjugating a TLR7/8 or TLR7 agonist to HER2 and CD20 tumor-targeting antibodies. ISACs were well tolerated and triggered a localized immune response in the TME, resulting in potent antitumor activity in xenograft and syngeneic tumor models. Mechanistically, ISACs required tumor antigen binding, functional Fcγ receptors, and TLR agonist activation, resulting in myeloid APC activation and tumor infiltration, tumor cell killing, and subsequent T cell-mediated immunity with memory and epitope spreading.
Contributed by Katherine Turner
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.