Structure-Based Design of Novel TLR7/8 Agonist Payloads Enabling an Immunomodulatory Conjugate Approach
Dual activation of the TLR7 and TLR8 pathways leads to the production of type I interferon and proinflammatory cytokines, resulting in efficient antigen presentation by dendritic cells to promote T-cell priming and antitumor immunity. We developed a novel series of TLR7/8 dual agonists with varying ratios of TLR7 and TLR8 activity for use as payloads for an antibody-drug conjugate approach. The agonist-induced production of several cytokines in human whole blood confirmed their functional activity. Structure-activity relationship studies guided by structure-based drug design are described.
Authors
- Yam B. Poudel (ORCID: https://orcid.org/0000-0002-8694-1084)
- Ashvinikumar V. Gavai (ORCID: https://orcid.org/0000-0002-6067-4176)
- David Critton
- Payal Dhar (ORCID: https://orcid.org/0000-0001-5379-8675)
- Lakshumanan Subramani
- Arvind Mathur (ORCID: https://orcid.org/0000-0003-3146-8485)
- Chunshan Xie
- Derek Norris
- Emanuela Sega
- Dahlia R. Weiss (ORCID: https://orcid.org/0000-0003-1073-940X)
- Dawn Mulligan
- Shaily Jain (ORCID: https://orcid.org/0000-0001-6078-3607)
- Julian C. Lo
- Sayumi Yamazoe (ORCID: https://orcid.org/0000-0002-2169-7674)
- Christoph W. Zapf (ORCID: https://orcid.org/0000-0001-5153-5206)
- Soodamani Thangavel
- Prasanna Sivaprakasam (ORCID: https://orcid.org/0000-0002-4115-5055)
- Murugaiah A. M. Subbaiah (ORCID: https://orcid.org/0000-0001-5707-966X)
- Yvonne Li
- Liqi He
- Matthew Cox (ORCID: https://orcid.org/0000-0002-0172-2895)
- Eugene P. Chekler
- Maheswara Reddy
- Walter L. Johnson
- Santigopal Mondal
Institutions
- Bristol-Myers Squibb (United States) (US)
- Bristol-Myers Squibb (India) (IN)
- Biocon (India) (IN)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2024-12-19
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00463
- Citations
- 3
- Primary Topic
- Immune Response and Inflammation
- Type
- article
- Field-Weighted Citation Impact
- 0.72