Temporal cytokine and lymphoid responses to an inhaled TLR7 antedrug agonist in the cynomolgus monkey demonstrates potential safety and tolerability of this approach

摘要

Abstract AZD8848 is a TLR7 agonist antedrug developed for administration by inhalation dosing for the treatment of allergic diseases, such as asthma. Allergic asthma is associated with increased levels of Th2 cytokines which are suppressed for extended periods by TLR7 agonists in a number of preclinical models of allergic airway inflammation. However, TLRs form a central part of innate immunity and their activation often results in proinflammatory responses. Whilst AZD8848's antedrug mechanism is designed to restrict its pharmacological action beyond the lung, the effect of chronic, supramaximal dosing to the target tissue has yet to be defined. To support clinical development of this potentially disease modifying approach the nonclinical safety and pharmacodynamics of AZD8848 were evaluated in cynomolgus monkeys in studies examining single or multiple weekly inhaled doses. Here we show that following a single dose nearly all responses returned to baseline within a week. During multiple dosing serum biomarkers were quantified over the dosing period and indicated a limited systemic response. The dose at which maximal interferon responses were seen was dependent on dose. Thorough histopathological examination revealed a dose related increase of size and cells of lymphoid tissues in the lung and nose. Local lymphoid responses were recovered after the treatment free period. These studies are the first to evaluate safety of an inhaled TLR7 agonist and demonstrate AZD8848 is safe with a no observed adverse effect level at 26μg/kg allowing progression to man with weekly inhalation dosing. Highlights ? This is the first report of the safety of an inhaled TLR7 agonist. ? The TLR7 agonist, AZD8848, was administered to cynomolgus monkeys by inhalation. ? Induction of mediators were followed up to 2weeks after single doses. ? 14 once-weekly inhaled doses of AZD8848 induced no significant adverse reactions. ? Changes to local lung lymphoid tissue returned to baseline within 9–13weeks.