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Antibody-mediated neutralization of perfringolysin o for intracellular protein delivery.


ABSTRACT: 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.

SUBMITTER: Yang NJ 

PROVIDER: S-EPMC4876977 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Antibody-mediated neutralization of perfringolysin o for intracellular protein delivery.

Yang Nicole J NJ   Liu David V DV   Sklaviadis Demetra D   Gui Dan Y DY   Vander Heiden Matthew G MG   Wittrup K Dane KD  

Molecular pharmaceutics 20150504 6


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 re  ...[more]

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