1124 Discovery and evaluation of bicyclic peptides as modulators of pattern recognition receptors

Résumé fourni par la source

Background Toll-like receptor 3 (TLR3) is an intracellular pattern recognition receptor aimed at binding double stranded RNA, which leads to cellular activation and proinflammatory cytokine secretion. Modulation of TLR3 biology can have significant impact in oncology and autoimmunity indications. In immuno-oncology, TLR3 agonists have been deployed as adjuvants to activate immune cells such as type I conventional dendritic cells that can help initiate the adaptive immune response to the tumor. In autoimmunity, TLR3 antagonists have been aimed at reducing immune cell over-activation. Despite a potential broad utility, systemic dsRNA TLR3 agonists and existing antagonists have not demonstrated clinical success due to lack of targeting and toxicity resulting from systemic activation. Therefore, the need for new molecular approaches to influence the signaling of TLR3 is evident. Bicycle® peptides are small molecules that penetrate rapidly into tissues and solid tumors and have a short half-life compared to biologics, potentially reducing systemic toxicity due to reduced exposure time. Methods Using the Bicycle® phage display platform, we have identified several families of Bicycles that bind the TLR3 extracellular domain. Bicycles were evaluated for their ability to modulate TLR3 signaling using a TLR3-overexpressing reporter cell assay. Binding and agonism was also assessed in monocyte derived macrophages that endogenously express TLR3. Conclusions This system allowed us to more closely evaluate Bicycles’ ability to bind and modulate TLR3 signaling through known pathways leading to production of pro-inflammatory cytokines.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.