Design and Optimization of Selectivity-Tunable Toll-like Receptor 7/8 Agonists as Novel Antibody–Drug Conjugate Payloads
Akash M. Patel, Aarron Willingham, Alan C. Cheng, Daniela M. Tomazela, Eddie Bowman, Esther Kofman, Fan Zhang, Jianming Bao, Jillian R. Sanzone, Jonathan W Choy, John A. Flygare, Jin‐Hwan Han, Komal Pradhan, Madeleine E. Kieffer, Natalia Chernyak, Peyman Akbari, Ping Liu, Rimsha Mehmood, Saraswathi Naravula, Scott A. Hollingsworth, Bhagyashree Bhagwat, Simon B. Lang, W. Michael Seganish
Abstract
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.