Discovery of cell surface vimentin targeting mAb for direct disruption of GBM tumor initiating cells.

Hyangsoon Noh,Jun Yan,Konrad Gabrusiewicz,Amy B. Heimberger,Ling-Yuan Kong,Shulin Li,Sungguan Hong,Xueqing Xia

doi:10.18632/oncotarget.12458

Abstract

Intracellular vimentin overexpression has been associated with epithelial–mesenchymal transition, metastasis, invasion, and proliferation, but cell surface vimentin (CSV) is less understood. Furthermore, it remains unknown whether CSV can serve as a therapeutic target in CSV-expressing tumor cells. We found that CSV was present on glioblastoma multiforme (GBM) cancer stem cells and that CSV expression was associated with spheroid formation in those cells. A newly developed monoclonal antibody against CSV, 86C, specifically and significantly induced apoptosis and inhibited spheroid formation in GBM cells in vitro. The addition of 86C to GBM cells in vitro also led to rapid internalization of vimentin and decreased GBM cell viability. These findings were associated with an increase in caspase-3 activity, indicating activation of apoptosis. Finally, treatment with 86C inhibited GBM progression in vivo. In conclusion, CSV-expressing GBM cells have properties of tumor initiating cells, and targeting CSV with the monoclonal antibody 86C is a promising approach in the treatment of GBM.

Highlights

Monoclonal antibody therapeutics are showing clinical and commercial success after intense research and development over the past 30 years [1]
We found that cell surface vimentin (CSV) was present on glioblastoma multiforme (GBM) cancer stem cells and that CSV expression was associated with spheroid formation in those cells
MAb therapies are proving useful in the treatment of diseases such as cancer, but the success of these therapies depends on the identification of suitable target proteins that play important roles in cancer progression and are homogenously over-expressed and accessible on the surface of tumor cells [20]

Summary

Introduction

Monoclonal antibody (mAb) therapeutics are showing clinical and commercial success after intense research and development over the past 30 years [1]. More than ten mAbs have been approved by the U.S Food and Drug Administration to treat cancer, and more than 100 mAbs are still under investigation in clinical trials in patients with cancer [2, 3] These anti-cancer antibodies do not necessarily cure cancer. Long-term treatment with mAbs can lead to intrinsic or acquired resistance [4] Cell surface receptors such as human epidermal growth factor 1(HER1), human epidermal growth factor receptor 2 (HER2), and CD20 as well as growth factors such as vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) are used as tumor targets of mAbs; these targets are found in normal cell proliferation and survival and are not ideal. Multiple clinical trials of therapies targeting vascular endothelial growth factor A or its receptors in patients with a variety of cancers have associated those therapies with only modest improvements in progressionfree or overall survival [5]

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