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Background <p>Thymic stromal lymphopoietin (TSLP) plays a pivotal role in immune responses. CM326 is a humanized monoclonal antibody targeting TSLP.</p> Objective <p>The aim of this study was to evaluate the preclinical characterization, safety, tolerability, pharmacokinetics, and immunogenicity of CM326 in healthy adults.</p> Methods <p>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&#xa0;mg), 4:1 (55/110/220/440/660/880&#xa0;mg), and 3:1 (330&#xa0;mg) to receive CM326 or placebo subcutaneously. Subjects in multiple ascending dose trials were randomized 4:1 (55/110/220&#xa0;mg every 2 weeks [Q2W], 220&#xa0;mg Q4W) and 3:1 (440&#xa0;mg Q2W) to receive CM326 or placebo.</p> Results <p>CM326 revealed higher potency over tezepelumab in blocking T<sub>h</sub>2-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&#xa0;mg. Mean accumulation ratio of AUC was 4.04, 3.87, and 3.74 for 55&#xa0;mg, 110&#xa0;mg, and 220&#xa0;mg Q2W after six doses and 2.16 for 440&#xa0;mg Q2W after three doses. The mean accumulation ratio of maximum concentration (<i>C</i><sub>max</sub>) was 3.66 and 1.52 for 220&#xa0;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.</p> Conclusions <p>CM326 improved T<sub>h</sub>2 inflammation preclinically and demonstrated an acceptable safety profile with linear pharmacokinetics and low immunogenicity in healthy adults.</p> Clinical Trial Registration <p>ClinicalTrials.gov identifiers: NCT04842201 (registered on 8 April 2021), NCT05171348 (registered on 9 December 2021), NCT05715333 (registered on 27 January 2023)</p>

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Translational Investigation of CM326 from Preclinical Studies to Randomized Phase I Clinical Trials in Healthy Adults

  • 期刊论文

  • 发表日期：

    2025年4月4日

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  • Yujing Di,
  • Ling Yang,
  • Jianfei Zhou,
  • Libo Zhang,
  • Yanqiu Huang,
  • Yingmin Jia,
  • Hongyue Yan,
  • Li Chen,
  • Qiaoyun Hou,
  • Bo Chen,
  • Zhu Luo,
  • Jie Hou

摘要

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 Th2-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 (Cmax) 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 Th2 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)