Pentelute Lab MIT | IgG-Engineered Protective Antigen for Cytosolic Delivery of Proteins into Cancer Cells
The Pentelute Lab aims to invent new chemistry for the efficient and selective modification of proteins, to ‘hijack’ these biological machines for efficient drug delivery into cells and to create new machines to rapidly and efficiently manufacture peptides and proteins.
Pentelute Lab, Chemistry, MIT, Chemistry Department, Boston, Cambridge, Biology, Peptides, Peptide, Proteins, Science, Rapid, Brad Pentelute, Brad,
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IgG-Engineered Protective Antigen for Cytosolic Delivery of Proteins into Cancer Cells

IgG-Engineered Protective Antigen for Cytosolic Delivery of Proteins into Cancer Cells

ACS Cent. Sci. 2021, 7, 2, 365–378 Publication Date:February 4, 2021 https://doi.org/10.1021/acscentsci.0c01670
Zeyu Lu, Nicholas L. Truex, Mariane B. Melo, Yiran Cheng, Na Li, Darrell J. Irvine, and Bradley L. Pentelute

Abstract

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.

Category
2021, Publications