Design and evaluation of a peptide-based immunotoxin for breast cancer therapeutics

• Published in: FEBS open bio 2015-01, Vol.5 (1), p.202-208
• Main Authors: Weigel, Kelsey J., Shen, Luqun, Thomas, Clayton L., Alber, Daniel, Drapalik, Lauren, Schafer, Zachary T., Lee, Shaun W.
• Format: Article
• Language: English
• Subjects: Apoptosis; Breast cancer; Cancer therapies; Chemotherapy; Cytokines; Cytotoxicity; Drug resistance; Epidermal growth factor; ErbB-2 protein; ErbB2-positive; Genetic engineering; Immunotoxin; Immunotoxins; Kinases; Peptides; Protein-tyrosine kinase receptors; Proteins; Therapeutics; Tumor cells; Tumors
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1016/j.fob.2015.03.005

•Chemotherapeutic resistance necessitates the development of new therapeutic options.•ErbB2 is overexpressed in approximately 30% of breast cancers.•We present a targeted immunotoxin peptide, termed NL1.1-PSA.•NL1.1-PSA has specific cytotoxicity toward ErbB2-overexpressing cells.•We validate a novel genetic engineering strategy for the production of immunotoxin peptides. Immunotoxins are chimeric proteins comprising a specific cellular targeting domain linked to a cytotoxic factor. Here we describe the design and use of a novel, peptide-based immunotoxin that can initiate selective cytotoxicity on ErbB2-positive cells. ErbB2 is a receptor tyrosine kinase that is overexpressed in the tumor cells of approximately 30% of breast cancer patients. Immunotoxin candidates were designed to incorporate a targeting ligand with affinity for ErbB2 along with a membrane lysin-based toxin domain. One particular peptide candidate, NL1.1-PSA, demonstrated selective cytotoxicity towards ErbB2-overexpressing cell lines. We utilized a bioengineering strategy to show that recombinant NL1.1-PSA immunotoxin expression by Escherichia coli also conferred selective cytotoxicity towards ErbB2-overexpressing cells. Our findings hold significant promise for the use of effective immunotoxins in cancer therapeutics.