Assessing antibody and nanobody nativeness for hit selection and humanization with AbNatiV
Assessing antibody and nanobody nativeness for hit selection and humanization with AbNatiV
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使用 AbNatiV 评估抗体和纳米抗体的天然性以进行命中选择和人源化
DOI：
10.1038/s42256-023-00778-3
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发表时间：
2024
影响因子：
23.8
通讯作者：
Ramon A
中科院分区：
文献类型：
--
作者：
Ramon A
单克隆抗体已成为关键的治疗方法。特别是纳米抗体，即在骆驼中天然表达的小型单域抗体，在2019年第一种纳米抗体药物获得批准后迅速发展。尽管如此，这些生物制剂作为治疗剂的发展仍然是一个挑战。尽管已经建立了相对快速和廉价的体外定向进化技术，但产生治疗性抗体的黄金标准仍然是从动物免疫或患者中发现。免疫系统衍生的抗体倾向于在体内具有有利的性质，包括长半衰期、与自身抗原的低反应性和低毒性。在这里，我们提出了AbNatiV，一种用于评估抗体和纳米抗体的天然性的深度学习工具，即它们属于免疫系统衍生的人类抗体或骆驼纳米抗体分布的可能性。AbNatiV是一种多用途工具，可准确预测来自任何来源的Fv序列的天然性，包括合成文库和计算设计。它提供了一个可解释的评分，预测免疫原性的可能性，以及一个残基水平的概况，可以指导抗体和纳米抗体的工程化，与免疫系统衍生的抗体和纳米抗体无法区分。我们进一步介绍了一个自动化的人源化管道，我们将其应用于两个纳米抗体。实验室实验表明，AbNatiV-人源化纳米抗体保持与其野生型相当或更好的结合和稳定性，不像使用常规结构和残基频率分析的人源化纳米抗体。我们将AbNatiV作为可下载软件和网络服务器提供。
Monoclonal antibodies have emerged as key therapeutics. In particular, nanobodies, small, single-domain antibodies that are naturally expressed in camelids, are rapidly gaining momentum following the approval of the first nanobody drug in 2019. Nonetheless, the development of these biologics as therapeutics remains a challenge. Despite the availability of established in vitro directed-evolution technologies that are relatively fast and cheap to deploy, the gold standard for generating therapeutic antibodies remains discovery from animal immunization or patients. Immune-system-derived antibodies tend to have favourable properties in vivo, including long half-life, low reactivity with self-antigens and low toxicity. Here we present AbNatiV, a deep learning tool for assessing the nativeness of antibodies and nanobodies, that is, their likelihood of belonging to the distribution of immune-system-derived human antibodies or camelid nanobodies. AbNatiV is a multipurpose tool that accurately predicts the nativeness of Fv sequences from any source, including synthetic libraries and computational design. It provides an interpretable score that predicts the likelihood of immunogenicity, and a residue-level profile that can guide the engineering of antibodies and nanobodies indistinguishable from immune-system-derived ones. We further introduce an automated humanization pipeline, which we applied to two nanobodies. Laboratory experiments show that AbNatiV-humanized nanobodies retain binding and stability at par or better than their wild type, unlike nanobodies that are humanized using conventional structural and residue-frequency analysis. We make AbNatiV available as downloadable software and as a webserver.
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