posted on 2024-01-08, 13:35authored byYam B. Poudel, Liqi He, Matthew Cox, Qian Zhang, Walter L. Johnson, Qiang Cong, Heng Cheng, Naidu S. Chowdari, Christine Tarby, Andrew F. Donnell, Matthais Broekema, Daniel P. O’Malley, Yong Zhang, Murugaiah A. M. Subbaiah, Boda Vijay Kumar, Lakshumanan Subramani, Bei Wang, Yi-Xin Li, Prasanna Sivaprakasam, David Critton, Dawn Mulligan, Bhupindar Sandhu, Chunshan Xie, Radha Ramakrishnan, Jignesh Nagar, Shailesh Dudhgaonkar, Martins S. Oderinde, Anwar Murtaza, Gary L. Schieven, Arvind Mathur, Ashvinikumar V. Gavai, Gregory Vite, Sanjeev Gangwar
We have designed and developed novel and selective TLR7
agonists
that exhibited potent receptor activity in a cell-based reporter assay. In vitro, these agonists significantly induced secretion
of cytokines IL-6, IL-1β, IL-10, TNFa, IFNa, and IP-10 in human
and mouse whole blood. Pharmacokinetic and pharmacodynamic studies
in mice showed a significant secretion of IFNα and TNFα
cytokines. When combined with aPD1 in a CT-26 tumor model, the lead
compound showed strong synergistic antitumor activity with complete
tumor regression in 8/10 mice dosed using the intravenous route. Structure–activity
relationship studies enabled by structure-based designs of TLR7 agonists
are disclosed.