Abstract：
Food allergy is a leading cause of anaphylaxis worldwide. Allergen-specific immunotherapy is the only treatment shown to modify the natural history of allergic disease, but application to food allergy has been hindered by risk of severe allergic reactions and short-lived efficacy. Allergen-derived peptides could provide a solution. PVX108 comprises seven short peptides representing immunodominant T-cell epitopes of major peanut allergens for treatment of peanut allergy.
Pre-clinical safety of PVX108 was assessed using ex vivo basophil activation tests (n = 185). Clinical safety and tolerability of single and repeat PVX108 doses were evaluated in a first-in-human, randomized, double-blind, placebo-controlled trial in peanut-allergic adults (46 active, 21 placebo). The repeat-dose cohort received six doses over 16 weeks with safety monitored to 21 weeks. Exploratory immunological analyses were performed at pre-dose, Week 21 and Month 18 after treatment.
PVX108 induced negligible activation of peanut-sensitised basophils. PVX108 was safe and well tolerated in peanut-allergic adults. There were no treatment-related hypersensitivity events or AEs of clinical concern. The only events occurring more frequently in active than placebo were mild injection site reactions. Exploratory immunological analyses revealed a decrease in the ratio of ST2+ Th2A:CCR6+ Th17-like cells within the peanut-reactive Th pool which strengthened following treatment.
This study supports the concept that PVX108 could provide a safe alternative to whole peanut immunotherapies and provides evidence of durable peanut-specific T-cell modulation. Translation of these findings to clinical efficacy in ongoing Phase 2 trials would provide important proof-of-concept for using peptides to treat food allergy.
Pre-clinical safety of PVX108 was assessed using ex vivo basophil activation tests (n = 185). Clinical safety and tolerability of single and repeat PVX108 doses were evaluated in a first-in-human, randomized, double-blind, placebo-controlled trial in peanut-allergic adults (46 active, 21 placebo). The repeat-dose cohort received six doses over 16 weeks with safety monitored to 21 weeks. Exploratory immunological analyses were performed at pre-dose, Week 21 and Month 18 after treatment.
PVX108 induced negligible activation of peanut-sensitised basophils. PVX108 was safe and well tolerated in peanut-allergic adults. There were no treatment-related hypersensitivity events or AEs of clinical concern. The only events occurring more frequently in active than placebo were mild injection site reactions. Exploratory immunological analyses revealed a decrease in the ratio of ST2+ Th2A:CCR6+ Th17-like cells within the peanut-reactive Th pool which strengthened following treatment.
This study supports the concept that PVX108 could provide a safe alternative to whole peanut immunotherapies and provides evidence of durable peanut-specific T-cell modulation. Translation of these findings to clinical efficacy in ongoing Phase 2 trials would provide important proof-of-concept for using peptides to treat food allergy.
摘要：
背景：食物过敏是全球过敏反应的主要原因。变应原特异性免疫疗法是唯一能改变过敏性疾病自然史的治疗方法。但是严重过敏反应的风险和短期疗效阻碍了对食物过敏的应用。过敏原来源的肽可以提供解决方案。PVX108包含7种代表主要花生变应原的免疫显性T细胞表位的短肽,用于治疗花生变态反应。
方法：使用离体嗜碱性粒细胞活化试验评估PVX108的临床前安全性（n=185）。临床安全性和耐受性的单一和重复的PVX108剂量进行了评估，在第一个人，随机化，双盲,花生过敏成人的安慰剂对照试验(46名活跃，21安慰剂）。重复剂量队列在16周内接受了6次剂量，安全性监测至21周。探索性免疫学分析在给药前进行，治疗后第21周和第18个月。
结果：PVX108对花生致敏嗜碱性粒细胞的活化作用可忽略不计。PVX108在花生过敏成人中是安全且耐受性良好的。没有治疗相关的超敏反应事件或临床关注的AE。与安慰剂相比，在活动中发生频率更高的唯一事件是轻度注射部位反应。探索性免疫学分析显示，花生反应性Th池中ST2Th2A：CCR6Th17样细胞的比例降低，治疗后增强。
结论：本研究支持PVX108可以提供全花生免疫疗法的安全替代方案，并提供了持久的花生特异性T细胞调节的证据。在正在进行的2期试验中将这些发现转化为临床疗效将为使用肽治疗食物过敏提供重要的概念证明。
方法：使用离体嗜碱性粒细胞活化试验评估PVX108的临床前安全性（n=185）。临床安全性和耐受性的单一和重复的PVX108剂量进行了评估，在第一个人，随机化，双盲,花生过敏成人的安慰剂对照试验(46名活跃，21安慰剂）。重复剂量队列在16周内接受了6次剂量，安全性监测至21周。探索性免疫学分析在给药前进行，治疗后第21周和第18个月。
结果：PVX108对花生致敏嗜碱性粒细胞的活化作用可忽略不计。PVX108在花生过敏成人中是安全且耐受性良好的。没有治疗相关的超敏反应事件或临床关注的AE。与安慰剂相比，在活动中发生频率更高的唯一事件是轻度注射部位反应。探索性免疫学分析显示，花生反应性Th池中ST2Th2A：CCR6Th17样细胞的比例降低，治疗后增强。
结论：本研究支持PVX108可以提供全花生免疫疗法的安全替代方案，并提供了持久的花生特异性T细胞调节的证据。在正在进行的2期试验中将这些发现转化为临床疗效将为使用肽治疗食物过敏提供重要的概念证明。
