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.

Advances in Anticancer Immunotoxin Therapy

“…Preclinical studies have suggested that this recombinant toxin is significantly less immunogenic than other payloads. Studies in mice demonstrated efficacy against EpCAM-positive solid tumors.VB6-845 caused severe vascular leak syndrome in rats at high doses but appeared to be better tolerated in cynomolgus monkeys [76]. A phase I study was opened in 2007 but closed for nonmedical reasons.…”

Depletion of T Cell Epitopes in Lysostaphin Mitigates Anti-Drug Antibody Response and Enhances Antibacterial Efficacy In Vivo

“…Empowered by advances in experimental methodologies (Mazor et al, 2012; Cantor et al, 2011; Harding et al, 2010), epitope prediction tools (Wang et al, 2010; Bryson et al, 2010; Jawa et al, 2013), and protein design algorithms (Parker et al, 2013; Choi et al, 2013, King et al, 2014), T cell epitope deletion is being applied to a progressively larger number of therapeutic candidates. Early clinical data from epitope depleted biotherapeutics suggests that molecular engineering has had the desired effect in human patients (Morris et al, 2005; Entwistle et al, 2012), although to date there is no comparative clinical data for T cell epitope depleted and wild type versions of the same biotherapeutic. Deimmunized variants of Pseudomonas exotoxin should soon be entering clinical trials (Mazor et al, 2014), and comparison to results with the wild type immunotoxin SS1P (Kreitman et al, 2009) will provide new insights into the clinical utility of T cell epitope deletion.…”

Addressing the Immunogenicity of the Cargo and of the Targeting Antibodies with a Focus on Deimmunized Bacterial Toxins and on Antibody-Targeted Human Effector Proteins

“…Efficacy studies in mice demonstrated that VB6-845 specifically and potently targeted EpCAM-positive tumors. High doses of VB6-845 administered to Cynomolgus monkeys were well-tolerated, and VB6-845 was proven to be minimally immunogenic in these monkeys [63]. …”