Antibody-Mediated Neutralization of Perfringolysin O for Intracellular Protein Delivery
Author(s)Yang, Nicole Jie Yeon; Liu, David V; Sklaviadis, Demetra; Wittrup, Karl Dane; Gui, Dan Yi; Vander Heiden, Matthew G.; ... Show more Show less
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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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Chemical Engineering
American Chemical Society (ACS)
Yang, Nicole J. et al. “Antibody-Mediated Neutralization of Perfringolysin O for Intracellular Protein Delivery.” Molecular Pharmaceutics 12.6 (2015): 1992–2000.
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