Discovery and\nEvaluation of TLR-Targeted Immune Agonists

Toll-like\nreceptor (TLR) activation converts immunologically\ninactive\ntumors into immunologically active tumors by activating tumor residing\nantigen-presenting cells and recruitment of cytotoxic T lymphocytes.\nTargeted immune agonists (TIAs) are antibody drug conjugates with\nsmall-molecule TLR agonist payloads. The mechanism of action of TIAs\ninvolves tumor antigen recognition, Fcγ-receptor-dependent phagocytosis,\nand TLR-mediated activation to drive tumor killing by myeloid cells.\nSeveral new low DAR anti-HER2 TIAs conjugated with novel TLR7 or dual-TLR7/8\nagonists with cleavable and noncleavable linkers were synthesized\nand profiled. In vitro studies demonstrated that these TIAs activate\nmyeloid cells only in the presence of antigen-expressing cancer cells.\nEvaluation in ELISpot-based assays confirmed the low immunogenicity\nof these constructs. Systemic administration of the novel TIAs in\ntumor-bearing mice resulted in tumor reduction at low doses. These\nresults provide a strong rationale for further development of the\nTIAs as a novel class of immunotherapeutics.