RT Journal Article
SR Electronic
T1 A robust and versatile nanobody platform for drug delivery
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.08.19.257725
DO 10.1101/2020.08.19.257725
A1 Zhuolun Shen
A1 Yufei Xiang
A1 Sandra Vegara
A1 Apeng Chen
A1 Zhengyun Xiao
A1 Ulises Santiago
A1 Changzhong Jin
A1 Zhe Sang
A1 Jiadi Luo
A1 Kong Chen
A1 Dina Schneidman-Duhovny
A1 Carlos Camacho
A1 Guillermo Calero
A1 Baoli Hu
A1 Yi Shi
YR 2020
UL http://biorxiv.org/content/early/2020/08/20/2020.08.19.257725.1.abstract
AB 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.Competing Interest StatementThe University of Pittsburgh has filed a provisional patent encompassing the technologies described in this manuscript.