Preclinical assessment of an anti-EpCAM immunotoxin: locoregional delivery provides a safer alternative to systemic administration.
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.
Brown
Jennifer
J
Viventia Biotechnologies, Inc., Winnipeg, Manitoba, Canada.
Rasamoelisolo
Michele
M
Spearman
Maureen
M
Bosc
Denis
D
Cizeau
Jeannick
J
Entwistle
Joycelyn
J
MacDonald
Glen C
GC
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
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