Antibody-Mediated Neutralization of Perfringolysin O for Intracellular Protein Delivery
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Antibody-mediated neutralization.pdf
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Author(s)
Yang, Nicole Jie Yeon
Sklaviadis, Demetra
Wittrup, Karl Dane
Gui, Dan Yi
Vander Heiden, Matthew G.
Liu, David V.
Date Issued
April 2015
Journal
Molecular Pharmaceutics
Publisher
American Chemical Society (ACS)
Citation
Yang, Nicole J. et al. “Antibody-Mediated Neutralization of Perfringolysin O for Intracellular Protein Delivery.” Molecular Pharmaceutics 12.6 (2015): 1992–2000.
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1021/mp500797n
