Clinical studies have suggested that human
epidermal growth factor receptor-2 (HER2) provide a useful target for antitumor
therapy. We previously described the generation of a chimeric HER2-targeted immunocasp-3
protein. In this study, we extend the repertoire of chimeric proapoptotic
proteins with
immunocasp-6, a construct that comprises a HER2-specific single-chain Ab, a single-chain Pseudomonas
exotoxin A, and an active
caspase-6, which can directly cleave
lamin A leading to nucleus damage and inducing programmed cell death. We demonstrate that the secreted
immunocasp-6 molecule selectively recognizes and induces apoptosis in HER2-overexpressing
tumor cells in vitro, but not in cells with undetectable HER2. The
immunocasp-6 gene was next transferred into BALB/c athymic mice bearing human breast SK-BR-3
tumors by i.m. injection of
liposome-encapsulated vectors, by intratumor injection of adenoviral vectors, or by i.v. injection of PBMC modified by retroviral
infection. Regardless of the method used, expression of
immunocasp-6 suppressed
tumor growth and prolonged animal survival significantly. Our data show that the chimeric
immunocasp-6 molecule can recognize HER2-positive
tumor cells, promptly attack their nucleus, and induce their apoptotic death, suggesting the potential of this strategy for the treatment of human
cancers that overexpress HER2.