Design and Optimization of Selectivity-Tunable Toll-like Receptor 7/8 Agonists as Novel Antibody-Drug Conjugate...

Area of Science:

• Immunology
• Pharmacology
• Oncology

Background:

• Toll-like receptors 7 and 8 (TLR7/8) play a crucial role in modulating innate and adaptive immune responses.
• Activation of TLR7/8 is a promising therapeutic strategy in immuno-oncology.
• Systemic administration of TLR7/8 agonists can lead to poor tolerance, necessitating alternative delivery methods.

Purpose of the Study:

• To identify and characterize novel, potent pyrazolopyrimidine-based TLR7/8 agonists with tunable receptor selectivity.
• To evaluate the potential of these agonists in immuno-oncology applications, particularly when delivered via antibody-drug conjugates (ADCs).

Main Methods:

• Synthesis and characterization of a novel series of pyrazolopyrimidine-based compounds.
• Assessment of agonist-induced cytokine and chemokine production from human peripheral blood mononuclear cells (PBMCs).
• Development and evaluation of anti-HER2 antibody-drug conjugates (ADCs) utilizing the identified TLR7/8 agonists as payloads in a THP1/N87 coculture system.

Main Results:

• A novel series of potent pyrazolopyrimidine-based TLR7/8 agonists with tunable selectivity was identified.
• These agonists successfully induced the production of pro-inflammatory cytokines and chemokines in human PBMCs.
• Anti-HER2 ADCs incorporating these payloads demonstrated mechanism-based activation of TLR7/8.

Conclusions:

• The identified pyrazolopyrimidine-based compounds represent a promising new class of TLR7/8 agonists.
• Targeted delivery via ADCs can mitigate systemic toxicity and enable localized immune activation.
• These findings support the development of novel immuno-oncology therapeutics leveraging TLR7/8 agonism.