Engineering the First Chimeric Antibody in Targeting Intracellular PRL-3 Oncoprotein for Cancer Therapy in Mice
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1 Denotes equal contribution
2 Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos, Singapore 138648, Republic of Singapore
3 Cleveland Clinic Lerner College of Medicine, 9500 Euclid Avenue, Cleveland, OH 44195, USA
4 Nanyang Technological University, School of Biological Sciences, 60 Nanyang Drive, Singapore 637551
5 Cancer Science Institute of Singapore, National University of Singapore, 28 Medical Drive, Singapore 117456
6 Department of Haematology-Oncology, National University Cancer Institute, Singapore National University Health System, 5 Lower Kent Ridge Road, S119074
7 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Republic of Singapore
Received: February 2, 2012; Accepted: February 21, 2012; Published: February 27, 2012;
Keywords: PRL-3 monoclonal antibody, PRL-3 mouse/human chimeric antibody, antibody therapy, intracellular oncoprotein
Antibodies are considered as ‘magic bullets’ because of their high specificity. It is believed that antibodies are too large to routinely enter the cytosol, thus antibody therapeutic approach has been limited to extracellular or secreted proteins expressed by cancer cells. However, many oncogenic proteins are localized within the cell. To explore the possibility of antibody therapies against intracellular targets, we generated a chimeric antibody targeting the intracellular PRL-3 oncoprotein to assess its antitumor activities in mice. Remarkably, we observed that the PRL-3 chimeric antibody could efficiently and specifically reduce the formation of PRL-3 expressing metastatic tumors. We further found that natural killer (NK) cells were important in mediating the therapeutic effect, which was only observed in a nude mouse model (T-cell deficient), but not in a Severe Combined Immunodeficiency’ (scid ) mouse model (B- and T-cell deficient), indicating the anticancer effect also depends on host B-cell activity. Our study involving 377 nude and scid mice suggest that antibodies targeting intracellular proteins can be developed to treat cancer.
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