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A resource of high-quality and versatile nanobodies for drug delivery.

ABSTRACT: Therapeutic and diagnostic efficacies of small biomolecules and chemical compounds are hampered by suboptimal pharmacokinetics. Here, we developed a repertoire of robust and high-affinity antihuman serum albumin nanobodies (Nb_HSA) that can be readily fused to small biologics for half-life extension. We characterized the thermostability, binding kinetics, and cross-species reactivity of Nb_HSAs, mapped their epitopes, and structurally resolved a tetrameric HSA-Nb complex. We parallelly determined the half-lives of a cohort of selected Nb_HSAs in an HSA mouse model by quantitative proteomics. Compared to short-lived control nanobodies, the half-lives of Nb_HSAs were drastically prolonged by 771-fold. Nb_HSAs have distinct and diverse pharmacokinetics, positively correlating with their albumin binding affinities at the endosomal pH. We then generated stable and highly bioactive Nb_HSA-cytokine fusion constructs "Duraleukin" and demonstrated Duraleukin's high preclinical efficacy for cancer treatment in a melanoma model. This high-quality and versatile Nb toolkit will help tailor drug half-life to specific medical needs.

SUBMITTER: Shen Z

PROVIDER: S-EPMC8426283 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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A resource of high-quality and versatile nanobodies for drug delivery.

Shen Zhuolun Z Xiang Yufei Y Vergara Sandra S Chen Apeng A Xiao Zhengyun Z Santiago Ulises U Jin Changzhong C Sang Zhe Z Luo Jiadi J Chen Kong K Schneidman-Duhovny Dina D Camacho Carlos C Calero Guillermo G Hu Baoli B Shi Yi Y

iScience 20210821 9

Therapeutic and diagnostic efficacies of small biomolecules and chemical compounds are hampered by suboptimal pharmacokinetics. Here, we developed a repertoire of robust and high-affinity antihuman serum albumin nanobodies (Nb<sub>HSA</sub>) that can be readily fused to small biologics for half-life extension. We characterized the thermostability, binding kinetics, and cross-species reactivity of Nb<sub>HSA</sub>s, mapped their epitopes, and structurally resolved a tetrameric HSA-Nb complex. We ...[more]

PMID: 34522857

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Project description:Sustained, localized protein delivery can enhance the safety and activity of protein drugs in diverse disease settings. While hydrogel systems are widely studied as vehicles for protein delivery, they often suffer from rapid release of encapsulated cargo, leading to a narrow duration of therapy, and protein cargo can be denatured by incompatibility with the hydrogel crosslinking chemistry. In this work, we describe injectable nanocomposite hydrogels that are capable of sustained, bioactive, release of a variety of encapsulated proteins. Injectable and porous cryogels were formed by bio-orthogonal crosslinking of alginate using tetrazine-norbornene coupling. To provide sustained release from these hydrogels, protein cargo was pre-adsorbed to charged Laponite nanoparticles that were incorporated within the walls of the cryogels. The presence of Laponite particles substantially hindered the release of a number of proteins that otherwise showed burst release from these hydrogels. By modifying the Laponite content within the hydrogels, the kinetics of protein release could be precisely tuned. This versatile strategy to control protein release simplifies the design of hydrogel drug delivery systems.Statement of significanceHere we present an injectable nanocomposite hydrogel for simple and versatile controlled release of therapeutic proteins. Protein release from hydrogels often requires first entrapping the protein in particles and embedding these particles within the hydrogel to allow controlled protein release. This pre-encapsulation process can be cumbersome, can damage the protein's activity, and must be optimized for each protein of interest. The strategy presented in this work simply premixes the protein with charged nanoparticles that bind strongly with the protein. These protein-laden particles are then placed within a hydrogel and slowly release the protein into the surrounding environment. Using this method, tunable release from an injectable hydrogel can be achieved for a variety of proteins. This strategy greatly simplifies the design of hydrogel systems for therapeutic protein release applications.

Dataset Information

A resource of high-quality and versatile nanobodies for drug delivery.

Publications

A resource of high-quality and versatile nanobodies for drug delivery.

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