ABSTRACT

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant morbidity and mortality worldwide. Despite a successful vaccination programme, the emergence of mutated variants that can escape current levels of immunity mean infections continue. Herein, we report the development of CT-P63, a broad-spectrum neutralizing monoclonal antibody. In vitro studies demonstrated potent neutralizing activity against the most prevalent variants, including Delta and the BA.1 and BA.2 sub-lineages of Omicron. In a transgenic mouse model, prophylactic CT-P63 significantly reduced wild-type viral titres in the respiratory tract and CT-P63 treatment proved efficacious against infection with Beta, Delta, and Omicron variants of SARS-CoV-2 with no detectable infectious virus in the lungs of treated animals. A randomized, double-blind, parallel-group, placebo-controlled, Phase I, single ascending dose study in healthy volunteers (NCT05017168) confirmed the safety, tolerability, and pharmacokinetics of CT-P63. Twenty-four participants were randomized and received the planned dose of CT-P63 or placebo. The safety and tolerability of CT-P63 were evaluated as primary objectives. Eight participants (33.3%) experienced a treatment-emergent adverse event (TEAE), including one grade ≥3 (blood creatine phosphokinase increased). There were no deaths, treatment-emergent serious adverse events, TEAEs of special interest, or TEAEs leading to study drug discontinuation in the CT-P63 groups. Serum CT-P63 concentrations rapidly peaked before declining in a biphasic manner and systemic exposure was dose proportional. Overall, CT-P63 was clinically safe and showed broad-spectrum neutralizing activity against SARS-CoV-2 variants in vitro and in vivo.

摘要

由严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 引起的大流行已导致全球严重的发病率和死亡率。尽管疫苗接种计划取得了成功，但可以逃避当前免疫水平的突变变体的出现意味着感染仍在继续。在此，我们报告了广谱中和单克隆抗体 CT-P63 的开发。体外研究表明对最普遍的变体具有有效的中和活性，包括 Omicron 的 Delta 和 BA.1 和 BA.2 亚谱系。在转基因小鼠模型中，预防性 CT-P63 显着降低了呼吸道中的野生型病毒滴度，并且 CT-P63 治疗被证明对 SARS-CoV-2 的 Beta、Delta 和 Omicron 变体感染有效，且未检测到感染性病毒治疗动物的肺。一项在健康志愿者中进行的随机、双盲、平行组、安慰剂对照、I 期单次递增剂量研究 (NCT05017168) 证实了 CT-P63 的安全性、耐受性和药代动力学。24 名参与者被随机分配并接受计划剂量的 CT-P63 或安慰剂。CT-P63的安全性和耐受性被评估为主要目标。八名参与者（33. 3%）经历了治疗中出现的不良事件（TEAE），包括一个≥3级（血肌酸磷酸激酶升高）。在 CT-P63 组中，没有死亡、治疗中出现的严重不良事件、特别感兴趣的 TEAE 或导致研究药物中止的 TEAE。血清 CT-P63 浓度在以双相方式下降之前迅速达到峰值，并且全身暴露与剂量成正比。总体而言，CT-P63 在临床上是安全的，并显示出对 SARS-CoV-2 变体的广谱中和活性 血清 CT-P63 浓度在以双相方式下降之前迅速达到峰值，并且全身暴露与剂量成正比。总体而言，CT-P63 在临床上是安全的，并显示出对 SARS-CoV-2 变体的广谱中和活性 血清 CT-P63 浓度在以双相方式下降之前迅速达到峰值，并且全身暴露与剂量成正比。总体而言，CT-P63 在临床上是安全的，并显示出对 SARS-CoV-2 变体的广谱中和活性体外和体内。