HER2-affitoxin: a potent therapeutic agent for the treatment of HER2-overexpressing tumors.

Abstract

PURPOSE:

Cancers overexpressing the HER2/neu gene are usually more aggressive and are associated with poor prognosis. Although trastuzumab has significantly improved the outcome, many tumors do not respond or acquire resistance to current therapies. To provide an alternative HER2-targeted therapy, we have developed and characterized a novel recombinant protein combining an HER2-specific Affibody and modified Pseudomonas aeruginosa exotoxin A (PE 38), which, after binding to HER2, is internalized and delivered to the cytosol of the tumor cell, where it blocks protein synthesis by ADP ribosylation of eEF-2.

EXPERIMENTAL DESIGN:

The effect of the Affitoxin on cell viability was assessed using CellTiter-Glo (Promega). To assess HER2-specific efficacy, athymic nude mice bearing BT-474 breast cancer, SK-OV-3 ovarian cancer, and NCI-N87 gastric carcinoma xenografts were treated with the Affitoxin (HER2- or Tag-specific), which was injected every third day. Affitoxin immunogenicity in female BALB/c mice was investigated using standard antibody production and splenocyte proliferation assays.

RESULTS:

In vitro experiments proved that HER2-Affitoxin is a potent agent that eliminates HER2-overexpressing cells at low picomolar concentrations. Therapeutic efficacy studies showed complete eradication of relatively large BT-474 tumors and significant effects on SK-OV-3 and NCI-N87 tumors. HER2-Affitoxin cleared quickly from circulation (T(1/2) < 10 minutes) and was well tolerated by mice at doses of 0.5 mg/kg and below. Immunogenicity studies indicated that HER2-Affitoxin induced antibody development after the third injected dose.

CONCLUSIONS:

Our findings showed that HER2-Affitoxin is an effective anticancer agent and a potential candidate for clinical studies.

• Authors: Rafal Zielinski, Ilya Lyakhov, Moinuddin Hassan, Monika Kuban, Kimberly Shafer-Weaver, Amir Gandjbakhche, Jacek Capala
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 15 Pg. 5071-81 (Aug 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21791637 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2011 AACR.

Chemical References

• Bacterial Toxins
• Exotoxins
• HER2 affitoxin
• Immunotoxins
• Recombinant Fusion Proteins
• Virulence Factors
• ADP Ribose Transferases
• Pseudomonas aeruginosa exotoxin A
• Receptor, ErbB-2

Topics

• ADP Ribose Transferases (administration & dosage)
• Animals
• Bacterial Toxins (administration & dosage)
• Cell Line, Tumor
• Exotoxins (administration & dosage)
• Immunotoxins (therapeutic use)
• Mice
• Mice, Nude
• Receptor, ErbB-2 (immunology, metabolism)
• Recombinant Fusion Proteins (therapeutic use)
• Virulence Factors (administration & dosage)
• Xenograft Model Antitumor Assays