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IgG-Engineered Protective Antigen for Cytosolic Delivery of Proteins into Cancer Cells
Name
acscentsci.0c01670.pdf
Description
Published version
Size
7.09 MB
Format
Adobe PDF
Checksum (MD5)
fa62f9e37479cdc062a9f98bbd560b54
Author(s)
Lu, Zeyu
Truex, Nicholas L
Melo, Mariane B
Cheng, Yiran
Li, Na
Irvine, Darrell J
Pentelute, Bradley L
Date Issued
2021
Journal
ACS Central Science
Publisher
American Chemical Society (ACS)
Version
Final published version
Abstract
© 2020 American Chemical Society. All rights reserved. Therapeutic immunotoxins composed of antibodies and bacterial toxins provide potent activity against malignant cells, but joining them with a defined covalent bond while maintaining the desired function is challenging. Here, we develop novel immunotoxins by dovetailing full-length immunoglobulin G (IgG) antibodies and nontoxic anthrax proteins, in which the C terminus of the IgG heavy chain is connected to the side chain of anthrax toxin protective antigen. This strategy enabled efficient conjugation of protective antigen variants to trastuzumab (Tmab) and cetuximab (Cmab) antibodies. The conjugates effectively perform intracellular delivery of edema factor and N terminus of lethal factor (LFN) fused with diphtheria toxin and Ras/Rap1-specific endopeptidase. Each conjugate shows high specificity for cells expressing human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), respectively, and potent activity across six Tmab- and Cmab-resistant cell lines. The conjugates also exhibit increased pharmacokinetics and pronounced in vivo safety, which shows promise for further therapeutic development.
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
10.1021/ACSCENTSCI.0C01670
