Antibody-Mediated Neutralization of Perfringolysin 0 for Intracellular Protein Delivery

作者：Yang Nicole J; Liu David V; Sklaviadis Demetra; Gui Dan Y; Vander Heiden Matthew G; Wittrup K Dane^*

来源：Molecular Pharmaceutics, 2015, 12(6): 1992-2000.

DOI：10.1021/mp500797n

• perfringolysin O
• cholesterol-dependent cytolysin
• intracellular delivery
• protein delivery
• endosomal release
• neutralizing antibody

Perfringolysin O (PFO) is a member of the cholesterol-dependent cytolysin (CDC) family of bacterial pore-forming proteins, which are highly efficient in delivering exogenous proteins to the cytoplasm. However, the indiscriminate and potent cytotoxicity of PFO limits its practical use as an intracellular delivery system. In this study, we describe the design and engineering of a bispecific, neutralizing antibody against PFO, which targets reversibly attenuated PFO to endocytic compartments via receptor-mediated internalization. This PFO-based system efficiently mediated the endosomal release of a co-targeted gelonin construct with high specificity and minimal toxicity in vitro. Consequently, the therapeutic window of PFO was improved by more than 5 orders of magnitude. Our results demonstrating that the activity of pore-forming proteins can be controlled by antibody-mediated neutralization present a novel strategy for utilizing these potent membrane-lytic agents as a safe and effective intracellular delivery vehicle.

• 出版日期2015-6
• 单位MIT