A new tumor-specific variant of GRP78 as target for antibody-based therapy

The chaperone GRP78 is a member of the heat-shock protein 70 (HSP70) family and is responsible for cellular homeostasis by preventing stress-induced apoptosis. GRP78 is expressed in all cells of the body. In malignant cells, which are permanently exposed to environmental stress, GRP78 is overexpressed and increased levels can be found in the cytoplasm and on the cell membrane. Thus, GRP78 promotes tumor proliferation, survival, metastases and resistance to a wide variety of therapies. Like other tumor-specific membrane molecules, GRP78 can also be present on cancer cells in a variant form. This modification qualifies it as a target for immune surveillance and antibody responses. The fully human monoclonal IgM antibody, SAM-6, was isolated from a gastric cancer patient and it binds to a new variant of GRP78 with a molecular weight of 82 kDa. The epitope is an O-linked carbohydrate moiety and is specific for malignant cells. These data show that cancer-specific modifications of cell-surface protection molecules are (a) subject of an immune response and (b) ideal targets for new therapeutical approaches.