Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology

Yam 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

doi:10.1021/acsmedchemlett.3c00455

Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology

ACS Med Chem Lett. 2024 Jan 8;15(2):181-188. doi: 10.1021/acsmedchemlett.3c00455. eCollection 2024 Feb 8.

Authors

Yam B Poudel¹, Liqi He¹, Matthew Cox¹, Qian Zhang¹, Walter L Johnson¹, Qiang Cong¹, Heng Cheng¹, Naidu S Chowdari¹, Christine Tarby², Andrew F Donnell², Matthais Broekema², Daniel P O'Malley², Yong Zhang², Murugaiah A M Subbaiah³, Boda Vijay Kumar³, Lakshumanan Subramani³, Bei Wang², Yi-Xin Li¹, Prasanna Sivaprakasam², David Critton², Dawn Mulligan², Bhupindar Sandhu², Chunshan Xie², Radha Ramakrishnan², Jignesh Nagar³, Shailesh Dudhgaonkar³, Martins S Oderinde², Anwar Murtaza², Gary L Schieven², Arvind Mathur², Ashvinikumar V Gavai², Gregory Vite², Sanjeev Gangwar¹

Affiliations

¹ Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
² Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
³ The Biocon Bristol Myers Squibb Research Center (BBRC), Bangalore 560099, India.

PMID: 38352830
PMCID: PMC10860183 (available on 2025-02-08)
DOI: 10.1021/acsmedchemlett.3c00455

Abstract

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.