A resource of high-quality and versatile nanobodies for drug delivery

Zhuolun Shen, Yufei Xiang, Sandra Vergara, Apeng Chen, Zhengyun Xiao, Ulises Santiago, Changzhong Jin, Zhe Sang, Jiadi Luo, Kong Chen, Dina Schneidman-Duhovny, Carlos Camacho, Guillermo Calero, Baoli Hu, Yi Shi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Therapeutic 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.

Original languageAmerican English
Article number103014
JournaliScience
Volume24
Issue number9
DOIs
StatePublished - 24 Sep 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors

Keywords

  • Biochemical Engineering
  • Biotechnology
  • Drug Delivery System
  • Proteomics
  • Structural Biology

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