Design and Optimization of Selectivity-Tunable Toll-like Receptor 7/8 Agonists as Novel Antibody–Drug Conjugate Payloads

Toll-like receptors 7 and 8 are involved in modulating
the adaptive
and innate immune responses, and their activation has shown promise
as a therapeutic strategy in the field of immuno-oncology. While systemic
exposure to TLR7/8 agonists can result in poor tolerance, combination
therapies and targeted delivery through antibody–drug conjugates
(ADCs) can help mitigate adverse effects. Described herein is the
identification of a novel and potent series of pyrazolopyrimidine-based
TLR7/8 agonists with tunable receptor selectivity. Representative
agonists from this series were successfully able to induce the production
of various proinflammatory cytokines and chemokines from human peripheral
blood mononuclear cells. Anti-HER2-25 and anti-HER2-26 ADCs made from this class of payloads demonstrated mechanism-based
activation of TLR7/8 in a THP1/N87 coculture system.