Design and Optimization of Selectivity-Tunable Toll-like Receptor 7/8 Agonists as Novel Antibody–Drug Conjugate Payloads
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-<b>25</b> and anti-HER2-<b>26</b> ADCs made from this class of payloads demonstrated mechanism-based activation of TLR7/8 in a THP1/N87 coculture system.
Authors
- Esther Kofman
- W. Michael Seganish (ORCID: https://orcid.org/0000-0001-6605-2856)
- Rimsha Mehmood (ORCID: https://orcid.org/0000-0002-2175-5133)
- Fan Zhang (ORCID: https://orcid.org/0000-0002-2418-1112)
- Simon B. Lang (ORCID: https://orcid.org/0000-0001-5380-2996)
- Saraswathi Naravula
- Jillian R. Sanzone (ORCID: https://orcid.org/0000-0003-2910-9889)
- Jonathan W Choy
- Scott A. Hollingsworth (ORCID: https://orcid.org/0000-0003-3294-0083)
- Natalia Chernyak (ORCID: https://orcid.org/0000-0002-3847-7360)
- Daniela M. Tomazela
- Akash M. Patel
- Madeleine E. Kieffer
- John A. Flygare
- Alan C. Cheng (ORCID: https://orcid.org/0000-0003-3645-172X)
- Ping Liu (ORCID: https://orcid.org/0000-0002-7171-7004)
- Jin‐Hwan Han (ORCID: https://orcid.org/0000-0003-2442-8442)
- Peyman Akbari
- Aarron Willingham
- Komal Pradhan (ORCID: https://orcid.org/0009-0007-2267-7505)
- Jianming Bao
- Bhagyashree Bhagwat
- Eddie Bowman
Institutions
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Biolog (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-08-22
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01384
- Citations
- 9
- Primary Topic
- Immune Response and Inflammation
- Type
- article
- Field-Weighted Citation Impact
- 2.16