2. Academic Validation
  3. Structure-Based Design of Novel TLR7/8 Agonist Payloads Enabling an Immunomodulatory Conjugate Approach

Structure-Based Design of Novel TLR7/8 Agonist Payloads Enabling an Immunomodulatory Conjugate Approach

  • ACS Med Chem Lett. 2024 Dec 19;16(1):80-88. doi: 10.1021/acsmedchemlett.4c00463.
Yam B Poudel 1,  Julian C Lo 1,  Derek J Norris 2,  Matthew Cox 1,  Liqi He 1,  Walter L Johnson 1,  Murugaiah A M Subbaiah 3,  Santigopal Mondal 3,  Soodamani Thangavel 3,  Lakshumanan Subramani 3,  Maheswara Reddy 3,  Suraksha Jain 3,  Dahlia R Weiss 1,  Prasanna Sivaprakasam 2,  David Critton 2,  Dawn Mulligan 2,  Chunshan Xie 2,  Payal Dhar 1,  Yvonne Li 1,  Emanuela Sega 1,  Sayumi Yamazoe 1,  Ashvinikumar V Gavai 2,  Arvind Mathur 2,  Christoph W Zapf 4,  Eugene P Chekler 1
Affiliations

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 Biocon Bristol Myers Squibb R&D Center (BBRC), Bangalore 560099, India.
  • 4 Bristol Myers Squibb Research & Development, 10300 Campus Point Drive, San Diego, California 92121, United States.
PMID: 39811121 DOI: 10.1021/acsmedchemlett.4c00463
Abstract

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.

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