A caspase-6 and anti-human epidermal growth factor receptor-2 (HER2) antibody chimeric molecule suppresses the growth of HER2-overexpressing tumors.
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.
Xu
Yan-Ming
YM
Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 17 Changle West Road, 710-032 Xi'an, China.
Wang
Li-Feng
LF
Jia
Lin-Tao
LT
Qiu
Xiu-Chun
XC
Zhao
Jing
J
Yu
Cui-Juan
CJ
Zhang
Rui
R
Zhu
Feng
F
Wang
Cheng-Ji
CJ
Jin
Bo-Quan
BQ
Chen
Si-Yi
SY
Yang
An-Gang
AG
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
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