Targeted Cytolysins Synergistically Potentiate Cytoplasmic Delivery of Gelonin Immunotoxin
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Wittrup_Targeted cytolysins.pdf
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Author(s)
Wittrup, K. D.
Pirie, Christopher M.
Liu, David V.
Wittrup, Karl Dane
Date Issued
July 2013
Journal
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research
Citation
Pirie, C. M., D. V. Liu, and K. D. Wittrup. “Targeted Cytolysins Synergistically Potentiate Cytoplasmic Delivery of Gelonin Immunotoxin.” Molecular Cancer Therapeutics 12, no. 9 (July 5, 2013): 1774–1782.
Version
Author's final manuscript
Abstract
Targeted endocytic uptake is a first step toward tissue-specific cytoplasmic macromolecular delivery; however, inefficient escape from the endolysosomal compartment makes this generally impractical at present. We report here a targeted cytolysin approach that dramatically potentiates endosomal release of an independently targeted potent gelonin immunotoxin. Fibronectin domains engineered for affinity to EGF receptor or carcinoembryonic antigen were fused to the plant toxin gelonin or bacterial pore-forming cytolysins. These fusion proteins display synergistic activity in both antigen-specific cytotoxicity in vitro, enhancing potency by several orders of magnitude, and in tumor growth inhibition in vivo. In addition, the number of internalized gelonin molecules required to induce apoptosis is reduced from approximately 5 × 106 to less than 103. Targeted potentiation shows promise for enhancing cytoplasmic delivery of other macromolecular payloads such as DNA, siRNA, and miRNA.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1158/1535-7163.mct-12-1023
