Ke Guo1,*, Jie Li1,*, Jing Ping Tang1,*, Cheng Peow Bobby Tan1, Cheng William Hong2, Abdul Qader O. Al-Aidaroos1,3, Leyon Varghese1, Caixia Huang1 and Qi Zeng1,4,†
* These authors contributed equally to this work.
1 - Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos, Singapore 138648.
2 - Cleveland Clinic Lerner College of Medicine, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
3 - Graduate School for Integrative Sciences and Engineering, National University of Singapore, 28 Medical Drive, Singapore 117456, Republic of Singapore.
4 - Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Republic of Singapore.
Journal: SCIENCE Translational Medicine 7 Sept, 2011 Vol. 3, Issue 99, p. 99ra85 DOI: 10.1126/scitranslmed.3002296 at http://stm.sciencemag.org/content/3/99/99ra85.abstract
Antibody-based therapies have better specificity and thus improved efficacy over standard chemotherapy regimens, which result in extended survival and improved quality of life for cancer patients. Because antibodies are viewed as too large to access intracellular locations, antibody therapy has traditionally targeted extracellular or secreted proteins expressed by cancer cells. However, many oncogenic proteins are found within the cell (such as intracellular phosphatases/kinases and transcription factors) and have therefore not been pursued for antibody therapies. Here, we explored the possibility of antibody therapy or vaccination against intracellular proteins. As proofs of concept, we selected three representative intracellular proteins as immunogens for tumor vaccine studies: PRL-3 (phosphatase of regenerating liver 3), a cancer-associated phosphatase; EGFP (enhanced green fluorescent protein), a general reporter; and mT (polyomavirus middle T), the polyomavirus middle T oncoprotein. A variety of tumors that expressed these intracellular proteins were clearly inhibited by their respective exogenous antibodies or by antigen-induced host antibodies (vaccination). These anticancer activities were reproducibly observed in hundreds of C57BL/6 tumor-bearing mice and MMTV-PymT transgenic breast tumor mice. Our in vivo data suggest that immunotherapies can target not only extracellular but also intracellular oncoproteins.
Figure Legends: PRL-3 mAb effectively inhibits metastatic tumours.
PRL-3 mAb effectively inhibits metastatic tumors formed by PRL-3 expressing B16F0 cancer cells but not PRL-3 non-expressing metastatic tumors formed by PRL-3 negative cells (B16F10). (A) Total cell lysates prepared from B16F0 and B16F10 melanoma cancer cells were tested for the expression of endogenous PRL-3 protein by immunoblot. GAPDH was used as a loading control. (B) C57BL/6 mice were injected with F0- or F10-cells and then followed by therapeutic schedules with PRL-3 mAb (treated) or PBS (untreated). (C) On around day 17, tumors were found at high frequency in the indicated tissues from ‘untreated’ F0-mice (n=5), while significantly reduced in ‘treated’ F0-mice (n=5). (D) Parallel experiments were performed with F10 melanoma cancer cell line for ‘treated’ (n=5) and ‘untreated’ F10-mice (n=5). (E-F) Using the student’s t-test, the differences in average body weights between PRL-3 mAb ‘treated’ or PBS ‘untreated’ mice showed significance increase in F0-recipients (p=0.017) but not in F10-recipients (p=0.187). P<0.05 was regarded statistically significant.
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