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A Caspase-6 and Anti-Human Epidermal Growth Factor Receptor-2 (HER2) Antibody Chimeric Molecule Suppresses the Growth of HER2-Overexpressing Tumors¹

Yan-Ming Xu^*, Li-Feng Wang^*, Lin-Tao Jia^*, Xiu-Chun Qiu^*, Jing Zhao^*, Cui-Juan Yu, Rui Zhang^*, Feng Zhu^*, Cheng-Ji Wang^*, Bo-Quan Jin, Si-Yi Chen and An-Gang Yang^2,*

Departments of ^* Biochemistry and Molecular Biology, and Immunology, Fourth Military Medical University, Xi’an, China; and Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030

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.

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