Brown Jennifer, Rasamoelisolo Michele, Spearman Maureen, Bosc Denis, Cizeau Jeannick, Entwistle Joycelyn, MacDonald Glen C
Viventia Biotechnologies, Inc., Winnipeg, Manitoba, Canada.
Cancer Biother Radiopharm. 2009 Aug;24(4):477-87. doi: 10.1089/cbr.2008.0579.
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.
VB4 - 845是一种重组免疫毒素，它由截短形式的铜绿假单胞菌外毒素A（ETA）与一个人源化单链抗体片段（4D5MOCB）基因连接而成，该单链抗体片段对上皮细胞粘附分子（EpCAM）具有特异性。EpCAM在多种人类肿瘤中过度表达，因此是免疫毒素治疗的合适靶抗原。临床前研究用于评估基于ETA的免疫毒素局部给药与全身给药的益处。在大鼠中重复皮下（s.c.）注射VB4 - 845（高达77.8微克/千克）除注射部位反应外，产生的不良反应极小，而重复全身给药则引发与血管渗漏综合征一致的症状。在食蟹猴中每周皮下注射该药物，产生的不良反应极小，仅限于注射部位反应，且1只动物出现肝酶短暂升高。毒代动力学表明该药物清除迅速，重复注射后第14天出现免疫反应。这些结果表明，VB4 - 845局部给药在安全性方面优于全身给药，对于适合局部给药途径的癌症可能是一种有效的替代方法。
