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.
Shen, Zhuolun and Xiang, Yufei and Vergara, Sandra and Chen, Apeng and Xiao, Zhengyun and Santiago, Ulises and Jin, Changzhong and Sang, Zhe and Luo, Jiadi and Chen, Kong and Schneidman, Dina and Camacho, Carlos J. and Calero, Guillermo and Hu, Baoli and Shi, Yi, A Resource of High-Quality Nanobodies for Drug Delivery. Available at SSRN: https://ssrn.com/abstract=3788460 or http://dx.doi.org/10.2139/ssrn.3788460
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