Genentech, Inc., South San Francisco, California,, USA.
Clin Pharmacol Ther. 2019 Jan;105(1):177-189. doi: 10.1002/cpt.1164. Epub 2018 Aug 12.
Most treatments for epithelial injury target hematopoietic mechanisms, possibly causing immunosuppression. Interleukin (IL)-22 promotes tissue regeneration, acting directly on epithelial cells. UTTR1147A, a human IL-22Fc (immunoglobulin G (IgG)4) fusion protein, activates IL-22 signaling. This phase I placebo-controlled trial of single, ascending, i.v. (1-120 μg/kg) and s.c (3-120 μg/kg) doses of UTTR1147A analyzed its effects on safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers in healthy volunteers. Most adverse events (AEs) were mild or moderate. The maximum tolerated i.v. dose in healthy volunteers was 90 μg/kg. Predominant AEs were dose-dependent reversible skin effects consistent with IL-22 pharmacology. UTTR1147A exposure increased approximately dose-proportionally, with a half-life of ~1 week. IL-22 biomarkers (regenerating islet protein 3A (REG3A), serum amyloid A (SAA), and C-reactive protein (CRP)) increased dose-dependently. Neither inflammatory symptoms and signs nor cytokines increased with CRP elevations. UTTR1147A demonstrated acceptable safety, pharmacokinetics, and IL-22R engagement, supporting further clinical development.
大多数针对上皮损伤的治疗方法都针对造血机制，可能导致免疫抑制。白细胞介素（IL）-22 可直接作用于上皮细胞，促进组织再生。UTTR1147A 是一种人 IL-22Fc（免疫球蛋白 G（IgG）4）融合蛋白，可激活 IL-22 信号通路。这项单剂量递增、静脉注射（1-120μg/kg）和皮下注射（3-120μg/kg）的 I 期安慰剂对照试验，分析了 UTTR1147A 在健康志愿者中的安全性、耐受性、药代动力学和药效学生物标志物的影响。大多数不良事件（AE）为轻度或中度。健康志愿者中静脉注射的最大耐受剂量为 90μg/kg。最常见的 AE 是与 IL-22 药理学一致的剂量依赖性可逆皮肤效应。UTTR1147A 的暴露量呈近似剂量比例增加，半衰期约为 1 周。IL-22 生物标志物（再生胰岛蛋白 3A（REG3A）、血清淀粉样蛋白 A（SAA）和 C 反应蛋白（CRP））呈剂量依赖性增加。CRP 升高时，无炎症症状和体征，细胞因子也无增加。UTTR1147A 表现出可接受的安全性、药代动力学和 IL-22R 结合，支持进一步的临床开发。
