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A Resource of High-Quality Nanobodies for Drug Delivery

37 Pages Posted: 18 Feb 2021 Publication Status: Review Complete

See all articles by Zhuolun Shen

Zhuolun Shen

University of Pittsburgh - Department of Cell Biology

Yufei Xiang

University of Pittsburgh - Department of Cell Biology

Sandra Vergara

University of Pittsburgh - Department of Structural Biology

Apeng Chen

University of Pittsburgh - Department of Neurological Surgery

Zhengyun Xiao

University of Pittsburgh - Department of Cell Biology

Ulises Santiago

University of Pittsburgh - Department of Computational and Systems Biology

Changzhong Jin

University of Pittsburgh - Department of Cell Biology

Zhe Sang

University of Pittsburgh - Department of Cell Biology

Jiadi Luo

University of Pittsburgh - Department of Medicine

Kong Chen

University of Pittsburgh - Department of Medicine

Dina Schneidman

University of Pittsburgh - Carnegie Mellon University Program in Computational Biology

Carlos J. Camacho

University of Pittsburgh - Department of Computational and Systems Biology

Guillermo Calero

University of Pittsburgh - Department of Structural Biology

Baoli Hu

University of Pittsburgh - Department of Neurological Surgery

Yi Shi

University of Pittsburgh - Department of Cell Biology

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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.

Suggested Citation

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
This version of the paper has not been formally peer reviewed.

Zhuolun Shen

University of Pittsburgh - Department of Cell Biology ( email )

United States

Yufei Xiang

University of Pittsburgh - Department of Cell Biology ( email )

United States

Sandra Vergara

University of Pittsburgh - Department of Structural Biology ( email )

135 N Bellefield Ave
Pittsburgh, PA 15260
United States

Apeng Chen

University of Pittsburgh - Department of Neurological Surgery ( email )

135 N Bellefield Ave
Pittsburgh, PA 15260
United States

Zhengyun Xiao

University of Pittsburgh - Department of Cell Biology ( email )

United States

Ulises Santiago

University of Pittsburgh - Department of Computational and Systems Biology

Pittsburgh, PA 15260
United States

Changzhong Jin

University of Pittsburgh - Department of Cell Biology

United States

Zhe Sang

University of Pittsburgh - Department of Cell Biology ( email )

United States

Jiadi Luo

University of Pittsburgh - Department of Medicine ( email )

United States

Kong Chen

University of Pittsburgh - Department of Medicine

United States

Dina Schneidman

University of Pittsburgh - Carnegie Mellon University Program in Computational Biology ( email )

135 N Bellefield Ave
Pittsburgh, PA 15260
United States

Carlos J. Camacho

University of Pittsburgh - Department of Computational and Systems Biology

Pittsburgh, PA 15260
United States

Guillermo Calero

University of Pittsburgh - Department of Structural Biology ( email )

135 N Bellefield Ave
Pittsburgh, PA 15260
United States

Baoli Hu

University of Pittsburgh - Department of Neurological Surgery ( email )

135 N Bellefield Ave
Pittsburgh, PA 15260
United States

Yi Shi (Contact Author)

University of Pittsburgh - Department of Cell Biology ( email )

United States

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