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2A peptide-based, lentivirus-mediated anti-death receptor 5 chimeric antibody expression prevents tumor growth in
1Department 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.
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.
Insights
Researchers developed a novel lentivirus-delivered chimeric antibody targeting DR5, demonstrating significant tumor cell killing and inhibiting tumor growth in mice. This antibody shows promise as an anticancer therapy and in combination with chemotherapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) pathway is crucial for targeted tumor cell death.
- TRAIL receptors are promising targets for antibody-mediated cancer therapy due to their specificity for tumor cells.
- Developing effective antibody delivery systems is key for successful cancer treatment.
Purpose of the Study:
- To create a novel chimeric antibody (zaptuximab) targeting DR5 using a lentivirus vector.
- To evaluate the in vitro and in vivo anti-tumor efficacy of lentivirus-expressed zaptuximab.
- To investigate the synergistic effect of zaptuximab with chemotherapy.
Main Methods:
- Construction of a lentivirus vector expressing a chimeric anti-DR5 antibody (zaptuximab) via a 2A/furin peptide.
- Assessment of zaptuximab binding specificity to DR5 and its apoptosis-inducing activity in tumor cell lines.
- Evaluation of in vivo anti-tumor efficacy in mouse models of human colon and lung cancer, including combination therapy with mitomycin C (MMC).
Main Results:
- Lentivirus-expressed zaptuximab specifically bound to DR5 and induced significant apoptosis in various tumor cell lines.
- The recombinant virus lenti-HF2AL demonstrated potent in vitro apoptosis-inducing activity.
- Subcutaneous human colon tumor growth in mice was significantly inhibited, and combination with MMC showed synergistic anti-tumor effects and prolonged survival in lung cancer models.
Conclusions:
- Lentivirus-mediated expression of a 2A peptide-based anti-DR5 chimeric antibody (zaptuximab) exhibits potent anti-tumor activity.
- This approach holds potential for clinical application as an anticancer treatment.
- Zaptuximab may serve as a valuable adjuvant therapy when combined with chemotherapy.
