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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-023-02659-z

摘要内容如下：

75%以上的可归因于疟疾的死亡发生在5岁以下的儿童中。然而，世界卫生组织（WHO）推荐用于儿科的第一种疟疾疫苗RTS，S/AS01（Mosquirix）效力一般。包括单克隆抗体在内的补充战略在根除疟疾的努力中将是重要的。在这里，我们描述了45RTS，S/AS01疫苗接种者的循环B细胞库，并发现了用于开发潜在治疗剂的单克隆抗体。我们产生了超过28，000个抗体序列，并在体内测试了481个抗体的结合活性和125个抗体的抗疟活性。通过这些分析，我们确定了相关性，表明恶性疟原虫环子孢子蛋白（RTS中的靶抗原，S/AS01）中的序列可能诱导免疫显性抗体反应，从而限制更具保护性但不是显性的反应。使用结合研究、小鼠疟疾模型、生物制造评估和蛋白质稳定性分析，我们选择AB-000224和AB-007088作为临床先导和后备。我们对两种抗体的可变域（Fv）进行了改造，使其能够低成本大规模生产，以分发给儿科人群，符合世卫组织的首选产品指南。具有最佳生产和药物特性的工程克隆MAM01已进入临床开发阶段。

英文原文如下：

Abstracts

Over 75% of malaria-attributable deaths occur in children under the age of 5 years. However, the first malaria vaccine recommended by the World Health Organization (WHO) for pediatric use, RTS,S/AS01 (Mosquirix), has modest efficacy. Complementary strategies, including monoclonal antibodies, will be important in efforts to eradicate malaria. Here we characterize the circulating B cell repertoires of 45 RTS,S/AS01 vaccinees and discover monoclonal antibodies for development as potential therapeutics. We generated >28,000 antibody sequences and tested 481 antibodies for binding activity and 125 antibodies for antimalaria activity in vivo. Through these analyses we identified correlations suggesting that sequences in Plasmodium falciparum circumsporozoite protein, the target antigen in RTS,S/AS01, may induce immunodominant antibody responses that limit more protective, but subdominant, responses. Using binding studies, mouse malaria models, biomanufacturing assessments and protein stability assays, we selected AB-000224 and AB-007088 for advancement as a clinical lead and backup. We engineered the variable domains (Fv) of both antibodies to enable low-cost manufacturing at scale for distribution to pediatric populations, in alignment with WHO's preferred product guidelines. The engineered clone with the optimal manufacturing and drug property profile, MAM01, was advanced into clinical development.

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