【摘 要】
：
Toll-like receptors (TLRs) 7,8,and 9 belong to a family of pathogen-associated molecular pattern (PAMP) recognition receptors.These receptors have been shown to be expressed in endosomal membranes of
【机 构】
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Discovery Idera Pharmaceuticals USA
【出 处】
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中国上海第七届国际新药发明科技年会
论文部分内容阅读
Toll-like receptors (TLRs) 7,8,and 9 belong to a family of pathogen-associated molecular pattern (PAMP) recognition receptors.These receptors have been shown to be expressed in endosomal membranes of human B cells (TLR7 and 9),plasmacytoid dendritic cells (TLR7 and 9),monocytes (TLRS) and myeloid dendritic cells (TLR8).Viral and synthetic single-stranded RNAs act as ligands of TLR7 and TLR8,and bacterial,viral,and synthetic DNA containing unmethylated CpG motifs act as ligands of TLR9.Activation of TLR7,8 or 9 leads to Thl-type innate and adaptive immune responses.The agonists of TLR7,8,and 9 have broad application in the treatment of cancers,infections,asthma and allergies,and as adjuvants with DNA and protein vaccines.Through structure activity relationship studies of synthetic oligonucleotides,we have identified novel synthetic nucleotide motifs and oligonucleotide structures that modulate immune responses through TLR7,8,and 9.These studies have allowed us to create a portfolio of compounds with potent and different types of immune response profiles acting as agonists of TLR7,8,and 9.We have identified synthetic RNA-based compounds that act as agonists of TLR7 or TLR8 and as dual agonists of TLR7/8 and studied a dual TLR7/8 agonist candidate in preclinical mouse models for its antitumor and immunological activities.Currently,three of our synthetic agonists of TLR9,IMO-2055,IMO-2125,and IMO-2134 (QAX935) are under evaluation in clinical trials for cancers,infectious diseases,and respiratory diseases,respectively.Separately,we have also identified a novel DNA-based antagonist of TLR7 and TLR9,referred to as IMO-3100,as a lead candidate for development in autoimmune disease applications.
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