A robust and versatile nanobody platform for drug delivery

Shen, Z.; Xiang, Y.; Vergara, S.; Chen, A.; Xiao, Z.; Santiago, U.; Jin, C.; Sang, Z.; Luo, J.; Chen, K.; Schneidman-Duhovny, D.; Camacho, C. J.; Calero, G.; Hu, B.; Shi, Y.

doi:10.1101/2020.08.19.257725

bioRxiv · 10.1101/2020.08.19.257725

A robust and versatile nanobody platform for drug delivery

Shen, Z.·Xiang, Y.·Vergara, S.·Chen, A.·Xiao, Z.·Santiago, U.·Jin, C.·Sang, Z.·Luo, J.·Chen, K.·Schneidman-Duhovny, D.·Camacho, C. J.·Calero, G.·Hu, B.·Shi, Y.

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Abstract

Therapeutic and diagnostic efficacies of numerous small biomolecules and chemical compounds are hampered by the short half-lives. Here we report the development of a repertoire of diverse, high-affinity albumin-nanobodies (NbHSA) to facilitate drug delivery. By integrating biophysics, and hybrid structural biology, we have systematically characterized the NbHSA for albumin binding, mapped the epitopes, and resolved the architecture of a tetrameric Nb-albumin complex. We employed quantitative proteomics for accurate, multiplex Nb pharmacokinetic analysis. Using a humanized albumin mouse model, we found that the NbHSA has outstanding pharmacokinetics; the most stable NbHSA has a 771-fold T1/2 improvement compared with a control Nb. Interestingly, the pharmacokinetics of NbHSA is related to their biophysical and structural properties. To demonstrate the utility of NbHSA, we developed a highly stable NbHSA-hIL-2 cytokine conjugate "Duraleukin" and confirmed its improved anticancer properties than hIL-2 alone. We envision that this high-quality Nb resource will advance research into novel biotherapeutics.

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Shen, Z., Xiang, Y., Vergara, S., Chen, A., Xiao, Z., Santiago, U., Jin, C., Sang, Z., Luo, J., Chen, K., Schneidman-Duhovny, D., Camacho, C. J., Calero, G., Hu, B., Shi, Y.. 2020-08-20. A robust and versatile nanobody platform for drug delivery. https://doi.org/10.1101/2020.08.19.257725

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