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标题：A resource of high-quality and versatile nanobodies for drug delivery
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作者：Zhuolun Shen ; Yufei Xiang ; Sandra Vergara 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：9
页码：1-26
DOI：10.1016/j.isci.2021.103014
语种：English
出版社：Elsevier
摘要：SummaryTherapeutic and diagnostic efficacies of small biomolecules and chemical compounds are hampered by suboptimal pharmacokinetics. Here, we developed a repertoire of robust and high-affinity antihuman serum albumin nanobodies (NbHSA) that can be readily fused to small biologics for half-life extension. We characterized the thermostability, binding kinetics, and cross-species reactivity of NbHSAs, mapped their epitopes, and structurally resolved a tetrameric HSA-Nb complex. We parallelly determined the half-lives of a cohort of selected NbHSAs in an HSA mouse model by quantitative proteomics. Compared to short-lived control nanobodies, the half-lives of NbHSAs were drastically prolonged by 771-fold. NbHSAs have distinct and diverse pharmacokinetics, positively correlating with their albumin binding affinities at the endosomal pH. We then generated stable and highly bioactive NbHSA-cytokine fusion constructs “Duraleukin” and demonstrated Duraleukin's high preclinical efficacy for cancer treatment in a melanoma model. This high-quality and versatile Nb toolkit will help tailor drug half-life to specific medical needs.Graphical abstractDisplay OmittedHighlights•We provide a resource of high-affinity and versatile albumin nanobodies for drug delivery•We systematically map albumin nanobody epitopes by hybrid structural approaches•We parallelly measure the pharmacokinetics of nanobodies in a humanized mouse model•We develop nanobody-cytokine conjugates “Duraleukin” for cancer immunotherapyDrug delivery system; Biochemical engineering; Biotechnology; Structural biology; Proteomics