1. A Resource of High-Quality Nanobodies for Drug Delivery
- Author
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Yi Shi, Sandra Vergara, Dina Schneidman, Zhengyun Xiao, Zhe Sang, Yufei Xiang, Guillermo Calero, Apeng Chen, Zhuolun Shen, Jiadi Luo, Baoli Hu, Ulises Santiago, Kong Chen, Carlos J. Camacho, and Changzhong Jin
- Subjects
Pharmacokinetics ,Chemistry ,In vivo ,Quantitative proteomics ,Drug delivery ,Multiplex ,Computational biology ,Epitope ,Pharmacokinetic analysis - Abstract
Therapeutic and diagnostic efficacies of numerous small biomolecules and chemical compounds are hampered by poor pharmacokinetics. Here we developed a repertoire of distinct and high-affinity albumin-nanobodies (NbHSA) to facilitate drug delivery. Using biophysics and hybrid structural methods, we have systematically characterized the Nb repertoire, mapped the epitopes, and resolved the architecture of a tetrameric Nb-albumin complex. We employed quantitative proteomics for accurate and multiplex pharmacokinetic analysis of dozens of diverse and high-quality NbHSA and confirmed the most stable construct has a 771-fold T1/2 improvement compared to non-albumin binding Nbs. Interestingly, the pharmacokinetics of NbHSA is related to their biophysical and structural properties. To demonstrate the utility of NbHSA, we developed stable NbHSA-cytokine conjugates “Duraleukins” and confirmed the high anticancer efficacy of a Duraluekin in vivo. This high-quality Nb resource may help advance research into novel biotherapeutics.
- Published
- 2021