IgG-Engineered Protective Antigen for Cytosolic Delivery of Proteins into Cancer Cells
Author(s)
Lu, Zeyu; Truex, Nicholas L; Melo, Mariane B; Cheng, Yiran; Li, Na; Irvine, Darrell J; Pentelute, Bradley L; ... Show more Show less
DownloadPublished version (7.089Mb)
Publisher with Creative Commons License
Publisher with Creative Commons License
Creative Commons Attribution
Terms of use
Metadata
Show full item recordAbstract
© 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.
Date issued
2021-02Department
Massachusetts Institute of Technology. Department of Chemistry; Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Center for Environmental Health Sciences; Ragon Institute of MGH, MIT and Harvard; Massachusetts Institute of Technology. Department of Materials Science and Engineering; Massachusetts Institute of Technology. Department of Biological EngineeringJournal
ACS Central Science
Publisher
American Chemical Society (ACS)
ISSN
2374-7951