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A phase 1 trial of lipid-encapsulated mRNA encoding a monoclonal antibody with neutralizing activity against Chikungunya virus
Nature Medicine ( IF 82.9 ) Pub Date : 2021-12-09 , DOI: 10.1038/s41591-021-01573-6
Allison August 1 , Husain Z Attarwala 1 , Sunny Himansu 1 , Shiva Kalidindi 1 , Sophia Lu 1 , Rolando Pajon 1 , Shu Han 1 , Jean-Michel Lecerf 1 , Joanne E Tomassini 1 , Marjie Hard 1 , Leon M Ptaszek 2 , James E Crowe 3 , Tal Zaks 1
Affiliation  

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 0.6 mg kg−1, or two weekly doses at 0.3 mg kg−1. At 12, 24 and 48 h after single infusions, dose-dependent levels of CHKV-24 IgG with neutralizing activity were observed at titers predicted to be therapeutically relevant concentrations (≥1 µg ml−1) across doses that persisted for ≥16 weeks at 0.3 and 0.6 mg kg−1 (mean t1/2 approximately 69 d). A second 0.3 mg kg−1 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.



中文翻译:

编码具有中和基孔肯雅病毒活性的单克隆抗体的脂质包裹 mRNA 的 1 期试验

基孔肯雅病毒 (CHIKV) 感染会导致以发烧、皮疹和关节痛为特征的急性疾病,最多 50% 的患者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 月进行的这项 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,mRNA-1944 是一种脂质纳米颗粒包裹的信使 RNA,编码重和CHIKV 特异性单克隆中和抗体 CHKV-24 (NCT03829384) 的轻链。主要结果是评估在 18-50 岁的健康参与者中通过静脉输注递增剂量的 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。在这里,我们报告了 38 名健康参与者的预先指定的中期分析结果,这些参与者接受了 0.1、0.3 和 0.6 mg/kg 的静脉内单剂量 mRNA-1944 或安慰剂 可电离氨基脂质的血浆浓度和 CHKV-24 IgG 的血清浓度。在这里,我们报告了 38 名健康参与者的预先指定的中期分析结果,这些参与者接受了 0.1、0.3 和 0.6 mg/kg 的静脉内单剂量 mRNA-1944 或安慰剂 可电离氨基脂质的血浆浓度和 CHKV-24 IgG 的血清浓度。在这里,我们报告了 38 名健康参与者的预先指定的中期分析结果,这些参与者接受了 0.1、0.3 和 0.6 mg/kg 的静脉内单剂量 mRNA-1944 或安慰剂-1,或每周两次剂量为 0.3 mg kg -1。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,滴度预计为治疗相关浓度(≥1 µg ml -1),跨剂量持续 ≥ 16周0.3 和 0.6 mg kg −1(平均 t 1/2大约 69 天)。第二个 0.3 mg kg −1第一次给药后 1 周,CHKV-24 IgG 水平增加 1.8 倍。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,没有一个是严重的。据我们所知,mRNA-1944 是第一个在临床试验中显示体内表达和可检测的离体中和活性的 mRNA 编码单克隆抗体,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。

更新日期:2021-12-09
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