中国临床药学杂志

目的 进行新型破伤风单克隆抗体GR2001注射液Ⅰ/Ⅱ期临床试验，评价其在中国成年参与者中的安全性、耐受性、药动学特征、药效学特征和免疫原性。方法 采用多中心、随机、双盲、对照、多队列的临床试验设计，纳入中国健康成年参与者202例，进行GR2001注射液单药Ⅰ/Ⅱ期临床试验，包括剂量递增试验(Ⅰ期临床试验第1阶段：评价不同剂量GR2001注射液的安全性、耐受性)、GR2001注射液联合吸附破伤风疫苗相互作用试验(Ⅰ期临床试验第2阶段：评价不同剂量GR2001注射液联合吸附破伤风疫苗的安全性、耐受性)和GR2001注射液和破伤风人免疫球蛋白联合吸附破伤风疫苗的对比试验(Ⅱ期临床试验：比较不同剂量GR2001注射液和破伤风人免疫球蛋白联合或不联合吸附破伤风疫苗的药效学特征)。结果 共有200例参与者完成试验，均未发生重度、严重、导致退出和死亡的不良事件。200例参与者单次肌内注射不同剂量的GR2001注射液后，血药浓度在7.0～14.5 d达峰，药物暴露量随剂量升高，基本呈线性关系；联合吸附破伤风疫苗不改变其药动学特征。GR2001注射液起效迅速，联合或不联合吸附破伤风疫苗的抗破伤风毒素中和抗体阳性率均为100%，抗破伤风毒素中和抗体水平≥0.01 U·mL^-1能够自给药结束后24 h起维持整个试验周期。GR2001注射液单药使用未发现抗药抗体阳性，与吸附破伤风疫苗联用抗药抗体阳性率较低。结论 GR2001注射液对中国成年参与者的安全性和耐受性良好，药物暴露量随给药剂量增加，基本呈现线性特征，起效迅速，持续时间长，联用吸附破伤风疫苗对主动免疫的影响可控。

AIM To conduct the Phase Ⅰ/Ⅱ clinical trial of GR2001 injection, a novel anti-tetanus monoclonal antibody, and evaluate the dose-dependent safety, tolerability, pharmacokinetics(PK), pharmacodynamics(PD), and immunogenicity of the injection in adult Chinese participants. METHODS This clinical trial adopted a multicenter, randomized, double-blind, controlled, and multiple-cohort design, which enrolled 202 Chinese healthy adult participants. The first part was a single-agent dose-escalation trial of GR2001 injection(Stage 1, Phase Ⅰ). The primary objective was to evaluate the safety and tolerability of varying doses of GR2001 injection. Subsequently, a drug-vaccine interaction trial of GR2001 injection was conducted(Stage 2, Phase Ⅰ) to evaluate the safety and tolerability of different doses of GR2001 injection combined with adsorbed tetanus vaccine. Finally, a comparative trial of GR2001 injection plus vaccine versus human tetanus immunoglobulin(HTIG) plus vaccine(Phase Ⅱ) was performed to compare the pharmacodynamic profiles between different doses of GR2001 injection(with or without adsorbed tetanus vaccine) and HTIG(with or without adsorbed tetanus vaccine). RESULTS A total of 200 participants completed the trial. No severe, serious, withdrawalcausing, or fatal adverse events were reported. Following a single intramuscular injection of different doses of GR2001 injection, peak plasma drug concentrations were reached within 7.0 to 14.5 days, and systemic drug exposure increased nearly linearly with ascending doses. Co-administration with adsorbed tetanus vaccine did not alter its pharmacokinetic profile. GR2001 injection exerted a rapid onset of action. The positive rate of anti-tetanus toxin neutralizing antibodies reached 100% regardless of co-administration with two doses of tetanus toxoid vaccine. Neutralizing antibody levels ≥ 0.01 U/mL were sustained throughout the trial period, starting at 24 h post-administration. No positive anti-drug antibody(ADA) signals were detected when GR2001 injection was administered alone, while only a low ADA positive rate was observed in the combination group with adsorbed tetanus vaccine. CONCLUSION GR2001 injection demonstrates favorable safety and tolerability in Chinese adult participants. Systemic drug exposure increases in an approximately linear manner with rising doses. The product features rapid onset and long duration of effect, and its co-administration with adsorbed tetanus vaccine exerts manageable impacts on active immunization.