Effects of the Toll-like receptor 7 (TLR7) agonist, AZD8848, on allergen-induced responses in patients with mild asthma: a double-blind, randomised, parallel-group study

Leaker, Brian R.; Singh, Dave; Lindgren, Sam; Almqvist, Gun; Eriksson, Leif; Young, Barbara; O’Connor, Brian

Toll-like receptors (TLRs) play a key role within the innate immune system by recognising pathogenassociated molecular patterns (PAMPs) via a leucinerich pattern recognition receptor (PRR) domain [11, 12] . TLR7, primarily expressed by plasmacytoid dendritic cells, detects infection by single-stranded ribonucleic acid (ssRNA) viruses, including influenza, coronavirus and rhinovirus [13] . TLR7 activation triggers an innate immune response, with a signalling cascade involving the recruitment of Myeloid differentiation primary response 88 (MyD88), interleukin-1 receptor-associated kinase 1 (IRAK-1), interleukin-1 receptor-associated kinase 4 (IRAK-4), TNF receptor-associated factor 6 (TRAF6) and interferon regulatory factor 7 (IRF-7) [14] . Phosphorylated IRF-7 subsequently upregulates the production of the type I interferons (IFNs) which help regulate the activity of the immune system. TLR7 agonists have potential as a new treatment option for allergic asthma by reducing responsiveness to allergens. TLR7 agonists have been shown to upregulate Th1 responses and downregulate Th2 responses to allergens in murine models of allergic or chronic asthma through a variety of complex mechanisms, such as activating nuclear factor NF-κB pathway transcription factors to increase production of cytokines, including IL-12, chemokines and Type I IFNs such as IFNα; some also appear to depend on the type II IFNγ [15] [16] [17] [18] . AZD8848 is a novel TLR7 agonist being developed for the treatment of asthma and allergic rhinitis. In order to restrict the effects of the drug to the site of administration and to minimise any potential for side effects associated with systemic cytokine production, AZD8848 has been designed as an antedrug. This metabolically labile ester is topically active but is rapidly hydrolysed by butyrylcholinesterase to a much less active metabolite upon entry to the circulation [19] .