title: Preclinical evaluation of VB6-845: an anti-EpCAM immunotoxin with reduced immunogenic potential.
abstract: VB6-845 is a recombinant immunotoxin comprised of deBouganin (a de-immunized plant toxin) genetically linked to an epithelial cell adhesion molecule (EpCAM)-targeting humanized Fab fragment (4D5MOCB). EpCAM is highly expressed on a wide range of epithelial tumors but has limited expression on most normal epithelia and therefore represents an excellent target for immunotherapy. A comprehensive preclinical evaluation was performed to determine the safety and suitability of VB6-845 as a systemically administered drug for the treatment of solid tumors. Efficacy studies in mice demonstrated that VB6-845 specifically and potently targeted EpCAM-positive tumors. In a dose-ranging study in Sprague-Dawley rats, single doses of VB6-845 were well-tolerated resulting in a no-observable adverse effect level (NOAEL) of 100 mg/kg whereas repeated doses of VB6-845 resulted in vascular leak-associated symptoms particularly at higher dose levels. However, much higher doses in Cynomolgus monkeys were well-tolerated when given as a 3-hour infusion mimicking the intended route of administration in the clinic. In addition, VB6-845 proved to be minimally immunogenic in monkeys. The toxicological data obtained in Cynomolgus monkeys indicated an excellent safety profile with a NOAEL value of 30 mg/kg (equivalent to a 10 mg/kg dose in humans). These results are supportive of an exploratory Phase I trial.
authors.affiliation: Department of Research, Viventia Biotechnologies, Inc., Winnipeg, Manitoba, Canada. jentwistle@viventia.com
authors.forename: Joycelyn
authors.initials: J
authors.lastname: Entwistle
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Brown
authors.forename: Shilpa
authors.initials: S
authors.lastname: Chooniedass
authors.forename: Jeannick
authors.initials: J
authors.lastname: Cizeau
authors.forename: Glen C
authors.initials: GC
authors.lastname: MacDonald
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D000922:Immunotoxins / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D000922:Immunotoxins; D011993:Recombinant Fusion Proteins; C544011:VB6-845 fusion protein