title: 2A peptide-based, lentivirus-mediated anti-death receptor 5 chimeric antibody expression prevents tumor growth in nude mice.
abstract: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces tumor cell death via death receptors on target cells, without adverse effects on most normal cells. Its receptors are therefore an attractive target for antibody-mediated tumor therapy. Here, we report the creation of a lentivirus vector constructed by linking the heavy chain and the light chain of the antibody with a 2A/furin self-processing peptide in a single open reading frame that expresses a novel chimeric antibody (named as zaptuximab) with tumoricidal activity, which is consisted of the variable region of a mouse anti-human DR5 monoclonal antibody, AD5-10, and the constant region of human immunoglobulin G1. Lentivirus-expressed zaptuximab bound specifically to its antigen, DR5, and exhibited significant apoptosis-inducing activity in various tumor cell lines. The packaged recombinant virus lenti-HF2AL showed strong apoptosis-inducing activity in vitro. Meanwhile, inoculated subcutaneous human colon HCT116 tumor formation in nude mice were inhibited significantly. Moreover, there was a synergistic effect of mitomycin C (MMC) on the observed tumoricidal efficacy, prolonging the life span of nude mice with orthotopic human lung tumor cancers. These data suggest that lentivirus-mediated, 2A peptide-based anti-DR5 chimeric antibody expression may have clinical utility as an anticancer treatment and may represent a rational adjuvant therapy in combination with chemotherapy.
authors.affiliation: Department of Biochemistry and Molecular Biology, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.forename: Yaomin
authors.initials: Y
authors.lastname: Wu
authors.forename: Yuhe
authors.initials: Y
authors.lastname: Qiu
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yao
authors.forename: Shilian
authors.initials: S
authors.lastname: Liu
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Liu
authors.forename: Juan
authors.initials: J
authors.lastname: Shi
authors.forename: Dexian
authors.initials: D
authors.lastname: Zheng
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics*; D000915:Antibody Affinity; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D045683:Furin / Q000737:chemistry*; D015870:Gene Expression; D023061:Gene Order; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D045325:HCT116 Cells; D057809:HEK293 Cells; D018922:HL-60 Cells; D056945:Hep G2 Cells; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000235:genetics; D016086:Lentivirus / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016685:Mitomycin / Q000008:administration & dosage / Q000494:pharmacology; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D010455:Peptides / Q000235:genetics*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors* / Q000276:immunology; D020298:U937 Cells
chemical_list: D000911:Antibodies, Monoclonal; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D010455:Peptides; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D016685:Mitomycin; D045683:Furin