Targeted cell killing is required for effective treatment of
cancers. We previously described the generation of a chimeric immunocasp-3
protein and its potent selective antitumor activity (Jia, L. T., Zhang, L. H., Yu, C. J., Zhao, J., Xu, Y. M., Gui, J. H., Jin, M., Ji, Z. L., Wen, W. H., Wang, C. J., Chen, S. Y., and Yang, A. G. (2003)
Cancer Res. 63, 3257-3262). Here we extend the repertoire of another chimeric
pro-apoptotic protein immunoGrB, which comprises an anti-HER2 single-chain antibody, a Pseudomonas
exotoxin A translocation domain and active
granzyme B. Human
lymphoma Jurkat cells transfected with the immunoGrB gene expression vector were able to produce and secrete the chimeric
protein. The immunoGrB molecule selectively recognized and destroyed HER2-overexpressing
tumor cells both in vitro and in nude mouse after
intramuscular injection of the immunoGrB expression plasmid. Further in vivo study showed that
intravenous administration of immunoGrB gene-modified lymphocytes led to suppression of HER2-overexpressing
tumor growth and prolonged animal survival because of continuous secretion of immunoGrB molecules into blood and lymph fluid. These results demonstrate that the chimeric immunoGrB molecule, which is capable of antibody-directed targeting and
granzyme B-mediated killing, has therapeutic potential against HER2
tumors, especially in cases in which caspase-dependent apoptosis is inhibited.