title: A caspase-6 and anti-human epidermal growth factor receptor-2 (HER2) antibody chimeric molecule suppresses the growth of HER2-overexpressing tumors.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 17 Changle West Road, 710-032 Xi'an, China.
authors.forename: Yan-Ming
authors.initials: YM
authors.lastname: Xu
authors.forename: Li-Feng
authors.initials: LF
authors.lastname: Wang
authors.forename: Lin-Tao
authors.initials: LT
authors.lastname: Jia
authors.forename: Xiu-Chun
authors.initials: XC
authors.lastname: Qiu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Cui-Juan
authors.initials: CJ
authors.lastname: Yu
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.forename: Cheng-Ji
authors.initials: CJ
authors.lastname: Wang
authors.forename: Bo-Quan
authors.initials: BQ
authors.lastname: Jin
authors.forename: Si-Yi
authors.initials: SY
authors.lastname: Chen
authors.forename: An-Gang
authors.initials: AG
authors.lastname: Yang
mesh_terms: D036002:ADP Ribose Transferases / Q000627:therapeutic use; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D017209:Apoptosis; D001427:Bacterial Toxins / Q000627:therapeutic use; D053178:Caspase 6; D020169:Caspases / Q000235:genetics*; D045744:Cell Line, Tumor; D005098:Exotoxins / Q000627:therapeutic use; D015316:Genetic Therapy; D006801:Humans; D019169:Jurkat Cells; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000737:chemistry / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D012190:Retroviridae / Q000235:genetics; D037521:Virulence Factors / Q000627:therapeutic use; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D000906:Antibodies; D001427:Bacterial Toxins; D053178:Caspase 6; D020169:Caspases; D005098:Exotoxins; D008081:Liposomes; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C543058:immunocasp-6; C505514:CASP6 protein, human; C505516:Casp6 protein, mouse