小柯机器人

美国Moderna公司Allison August团队报道了脂质体包裹mRNA可编码具有抗基孔肯雅病毒 (CHIKV)中和活性的单克隆抗体的1期试验。2021年12月9日，国际知名学术期刊《自然—医学》发表了这一成果。

CHIKV感染会导致以发烧、皮疹和关节痛为特征的急性疾病，在多达 50% 的患者中会发展为严重和慢性关节炎。此外，CHIKV 感染在婴儿或免疫功能低下的个体中可能是致命的，并且没有批准的治疗或预防措施。2019 年 1 月至 2020 年 6 月进行1期、首次人体、随机、安慰剂对照、概念验证试验评估了 mRNA-1944 的安全性和药理学，这是一种脂质纳米颗粒封装的信使 RNA，编码CHIKV 特异性单克隆中和抗体 CHKV-24 (NCT03829384) 的重链和轻链。

主要结果是评估 18-50 岁健康参与者通过静脉注射递增剂量的 mRNA-1944 的安全性和耐受性。次要目标包括确定编码 CHKV-24 免疫球蛋白重链和轻链以及可电离氨基脂质成分的 mRNA 的药代动力学，以及通过编码 CHKV-24 免疫球蛋白 G (IgG) 的 mRNA 的血清浓度评估的 mRNA-1944 的药效学，可电离氨基脂质的血浆浓度和 CHKV-24 IgG 的血清浓度。

他们报告了对38 名健康参与者进行预先指定的中期分析的结果，这些参与者接受了 0.1、0.3 和 0.6 mg kg-1 的静脉单剂量 mRNA-1944 或安慰剂，或每周两次 0.3 mg kg-1 的剂量。在单次输注后 12、24 和 48 小时，观察到具有中和活性的 CHKV-24 IgG 的剂量依赖性水平，滴度预测为治疗相关浓度（≥1 µg ml-1），0.3 和 0.6 mg kg-1（平均 t1/2 约为 69 d）的整个剂量持续≥16 周。在第一次将 CHKV-24 IgG 水平增加 1.8 倍后 1 周，第二次使用0.3 mg kg-1 剂量。不良反应的严重程度为轻度至中度，第二次 mRNA-1944 剂量没有恶化，而且没有一个是严重的。

据悉，mRNA-1944 是第一个在临床试验中显示出体内表达和可检测的离体中和活性的 mRNA 编码的单克隆抗体，可能为 CHIKV 感染提供治疗选择。有必要进一步评估 mRNA-1944 在治疗 CHIKV 感染的临床试验中的潜在治疗用途。

附：英文原文

Title: A phase 1 trial of lipid-encapsulated mRNA encoding a monoclonal antibody with neutralizing activity against Chikungunya virus

Author: August, Allison, Attarwala, Husain Z., Himansu, Sunny, Kalidindi, Shiva, Lu, Sophia, Pajon, Rolando, Han, Shu, Lecerf, Jean-Michel, Tomassini, Joanne E., Hard, Marjie, Ptaszek, Leon M., Crowe, James E., Zaks, Tal

Issue&Volume: 2021-12-09

Abstract: Chikungunya virus (CHIKV) infection causes acute disease characterized by fever, rash and arthralgia, which progresses to severe and chronic arthritis in up to 50% of patients. Moreover, CHIKV infection can be fatal in infants or immunocompromised individuals and has no approved therapy or prevention. This phase 1, first-in-human, randomized, placebo-controlled, proof-of-concept trial conducted from January 2019 to June 2020 evaluated the safety and pharmacology of mRNA-1944, a lipid nanoparticle-encapsulated messenger RNA encoding the heavy and light chains of a CHIKV-specific monoclonal neutralizing antibody, CHKV-24 (NCT03829384). The primary outcome was to evaluate the safety and tolerability of escalating doses of mRNA-1944 administered via intravenous infusion in healthy participants aged 18–50 years. The secondary objectives included determination of the pharmacokinetics of mRNA encoding for CHKV-24 immunoglobulin heavy and light chains and ionizable amino lipid component and the pharmacodynamics of mRNA-1944 as assessed by serum concentrations of mRNA encoding for CHKV-24 immunoglobulin G (IgG), plasma concentrations of ionizable amino lipid and serum concentrations of CHKV-24 IgG. Here we report the results of a prespecified interim analysis of 38 healthy participants who received intravenous single doses of mRNA-1944 or placebo at 0.1, 0.3 and 0.6mgkg1, or two weekly doses at 0.3mgkg1. At 12, 24 and 48h after single infusions, dose-dependent levels of CHKV-24 IgG with neutralizing activity were observed at titers predicted to be therapeutically relevant concentrations (≥1 μgml1) across doses that persisted for ≥16 weeks at 0.3 and 0.6mgkg1 (mean t1/2 approximately 69d). A second 0.3mgkg1 dose 1 week after the first increased CHKV-24 IgG levels 1.8-fold. Adverse effects were mild to moderate in severity, did not worsen with a second mRNA-1944 dose and none were serious. To our knowledge, mRNA-1944 is the first mRNA-encoded monoclonal antibody showing in vivo expression and detectable ex vivo neutralizing activity in a clinical trial and may offer a treatment option for CHIKV infection. Further evaluation of the potential therapeutic use of mRNA-1944 in clinical trials for the treatment of CHIKV infection is warranted.

DOI: 10.1038/s41591-021-01573-6

Source: https://www.nature.com/articles/s41591-021-01573-6

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
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