Preclinical assessment of an anti-EpCAM immunotoxin: locoregional delivery provides a safer alternative to systemic administration.

Abstract

VB4-845 is a recombinant immunotoxin that is comprised of a truncated form of Pseudomonas exotoxin A (ETA) genetically-linked to a humanized scFv fragment, (4D5MOCB), specific to epithelial cell adhesion molecule (EpCAM). EpCAM is overexpressed on a wide variety of human tumors and thus represents a suitable target antigen for immunotoxin therapy. Preclinical studies were used to evaluate the benefit of locoregional administration of an ETA-based immunotoxin versus systemic delivery. Repeated subcutaneous (s.c.) administration of VB4-845 (up to 77.8 microg/kg) in rats resulted in minimal adverse effects, except for injection-site reactions, while repeated systemic administration elicited symptoms consistent with vascular leak syndrome. S.c. weekly doses of the drug in cynomolgus monkeys resulted in minimal adverse effects limited to injection-site reactions and a transient elevation of liver enzymes in 1 animal. Toxicokinetics showed rapid clearance of the drug, with the development of an immune response by day 14 following repeated injections. These results argue that the local administration of VB4-845 has advantages with respect to safety over systemic administration and may be an effective alternative method for targeting those cancers that are amenable to local routes of administration.

• Authors: Jennifer Brown, Michele Rasamoelisolo, Maureen Spearman, Denis Bosc, Jeannick Cizeau, Joycelyn Entwistle, Glen C MacDonald
• Journal: Cancer biotherapy & radiopharmaceuticals (Cancer Biother Radiopharm) Vol. 24 Issue 4 Pg. 477-87 (Aug 2009) ISSN: 1557-8852 [Electronic] United States
• PMID: 19694583 (Publication Type: Journal Article)

Chemical References

• Antigens, Neoplasm
• Bacterial Toxins
• Cell Adhesion Molecules
• Epithelial Cell Adhesion Molecule
• Exotoxins
• Immunotoxins
• Virulence Factors
• ADP Ribose Transferases
• Pseudomonas aeruginosa exotoxin A

Topics

• ADP Ribose Transferases (administration & dosage)
• Animals
• Antigens, Neoplasm (immunology)
• Bacterial Toxins (administration & dosage)
• Cell Adhesion Molecules (immunology)
• Cell Line, Tumor
• Epithelial Cell Adhesion Molecule
• Exotoxins (administration & dosage)
• Haplorhini
• Humans
• Immunotoxins (administration & dosage, immunology, pharmacokinetics, toxicity)
• Infusions, Subcutaneous
• Neoplasms (drug therapy, immunology)
• Rats
• Rats, Sprague-Dawley
• Virulence Factors (administration & dosage)