title: 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.affiliation: Viventia Biotechnologies, Inc., Winnipeg, Manitoba, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brown
authors.forename: Michele
authors.initials: M
authors.lastname: Rasamoelisolo
authors.forename: Maureen
authors.initials: M
authors.lastname: Spearman
authors.forename: Denis
authors.initials: D
authors.lastname: Bosc
authors.forename: Jeannick
authors.initials: J
authors.lastname: Cizeau
authors.forename: Joycelyn
authors.initials: J
authors.lastname: Entwistle
authors.forename: Glen C
authors.initials: GC
authors.lastname: MacDonald
mesh_terms: D036002:ADP Ribose Transferases / Q000008:administration & dosage*; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D001427:Bacterial Toxins / Q000008:administration & dosage*; D015815:Cell Adhesion Molecules / Q000276:immunology*; D045744:Cell Line, Tumor; D000071858:Epithelial Cell Adhesion Molecule; D005098:Exotoxins / Q000008:administration & dosage*; D000882:Haplorhini; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity; D055104:Infusions, Subcutaneous; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D037521:Virulence Factors / Q000008:administration & dosage*; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D000951:Antigens, Neoplasm; D001427:Bacterial Toxins; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D005098:Exotoxins; D000922:Immunotoxins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A