Molecular engineering of high affinity single-chain antibody fragment for endothelial targeting of proteins and nanocarriers in rodents and humans

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• 作者：Colin F. Greineder^a ; ^b ; ^{cgreineder@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Elizabeth D. Hood^a ; ^b ; Anning Yao^a ; ^b ; Makan Khoshnejad^a ; ^b ; Jake S. Brenner^a ; ^b ; Ian H. Johnston^c ; Mortimer Poncz^c ; Claudia Gottstein^d ; Vladimir R. Muzykantov^a ; ^b
• 关键词：Endothelial drug delivery ; Immunotargeting ; Single chain variable fragment ; PECAM-1
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：28 March 2016
• 年：2016
• 卷：226
• 期：Complete
• 页码：229-237
• 全文大小：1961 K

文摘

Endothelial cells (EC) represent an important target for pharmacologic intervention, given their central role in a wide variety of human pathophysiologic processes. Studies in lab animal species have established that conjugation of drugs and carriers with antibodies directed to surface targets like the Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1, a highly expressed endothelial transmembrane protein) help to achieve specific therapeutic interventions in ECs. To translate such “vascular immunotargeting” to clinical practice, it is necessary to replace antibodies by advanced ligands that are more amenable to use in humans. We report the molecular design of a single chain variable antibody fragment (scFv) that binds with high affinity to human PECAM-1 and cross-reacts with its counterpart in rats and other animal species, allowing parallel testing in vivo and in human endothelial cells in microfluidic model. Site-specific modification of the scFv allows conjugation of protein cargo and liposomes, enabling their endothelial targeting in these models. This study provides a template for molecular engineering of ligands, enabling studies of drug targeting in animal species and subsequent use in humans.