Background: Thymic stromal lymphopoietin (TSLP) plays a pivotal role in immune responses. CM326 is a humanized monoclonal antibody targeting TSLP.

Objective: The aim of this study was to evaluate the preclinical characterization, safety, tolerability, pharmacokinetics, and immunogenicity of CM326 in healthy adults.

Methods: In vitro pharmacologic activity of CM326 was compared with that of tezepelumab. In vivo efficacy of CM326 was assessed in allergic cynomolgus monkeys. Subjects in single ascending dose trials were randomized 2:1 (22 mg), 4:1 (55/110/220/440/660/880 mg), and 3:1 (330 mg) to receive CM326 or placebo subcutaneously. Subjects in multiple ascending dose trials were randomized 4:1 (55/110/220 mg every 2 weeks [Q2W], 220 mg Q4W) and 3:1 (440 mg Q2W) to receive CM326 or placebo.

Results: CM326 revealed higher potency over tezepelumab in blocking T_h2-driven inflammation in vitro and ameliorated lung function and normalized the inflammatory microenvironment in vivo. CM326 was well tolerated with no discernible safety signals. CM326 showed linear pharmacokinetics over the dose range 22-880 mg. Mean accumulation ratio of AUC was 4.04, 3.87, and 3.74 for 55 mg, 110 mg, and 220 mg Q2W after six doses and 2.16 for 440 mg Q2W after three doses. The mean accumulation ratio of maximum concentration (C_max) was 3.66 and 1.52 for 220 mg Q2W and Q4W, respectively. Anti-drug antibodies (ADAs) were positive in 2/58 subjects after a single dose of CM326, 2/12 receiving placebo and 3/44 receiving CM326 after multiple doses.

Conclusions: CM326 improved T_h2 inflammation preclinically and demonstrated an acceptable safety profile with linear pharmacokinetics and low immunogenicity in healthy adults.

Clinical trial registration: ClinicalTrials.gov identifiers: NCT04842201 (registered on 8 April 2021), NCT05171348 (registered on 9 December 2021), NCT05715333 (registered on 27 January 2023).

© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

背景：

胸腺基质淋巴细胞生成素（TSLP）在免疫反应中发挥关键作用。CM326是一种针对TSLP的人源化单克隆抗体。

目的：

本研究旨在评估CM326在健康成人中的临床前特征、安全性、耐受性、药代动力学和免疫原性。

方法：

体外药物活性比较了CM326与tezepelumab的效果。通过过敏恒河猴模型评估了CM326的体内疗效。单次递增剂量试验中，受试者以2:1（22毫克）、4:1（55/110/220/440/660/880毫克）和3:1（330毫克）的比例随机接受CM326或安慰剂皮下注射。多次递增剂量试验中，受试者以4:1（每两周一次55/110/220毫克[Q2W]，每四周一次220毫克[Q4W]）和3:1（每次Q2W 440毫克）的比例随机接受CM326或安慰剂。

结果：

与tezepelumab相比，CM326在体外阻断T_h2驱动的炎症方面表现出更高的效力，并且在体内改善了肺功能并恢复了炎性微环境。CM326具有良好耐受性，未发现明显安全信号。CM326在剂量范围为22-880毫克时显示出线性药代动力学特性。六次给药后55毫克、110毫克和220毫克Q2W的平均AUC累积比分别为4.04、3.87和3.74，三次给药后的440毫克Q2W的平均累积比为2.16。对于220毫克Q2W和Q4W的最大浓度（C_max），其平均累积比分别为3.66和1.52。单次剂量CM326后，有2/58名受试者的抗药抗体（ADAs）呈阳性；接受安慰剂的12名受试者中有2名以及多次给药后的44名受试者中3名呈阳性。

结论：

CM326在临床前研究中改善了T_h2炎症，并展示了健康成人中的可接受安全特性、线性药代动力学和低免疫原性。

临床试验注册：

ClinicalTrials.gov编号：NCT04842201（于2021年4月8日注册），NCT05171348（于2021年12月9日注册），NCT05715333（于2023年1月27日注册）。

© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.