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.

Lipids are essential for normal and malignant cells during growth and differentiation. The turnover is strictly regulated because an uncontrolled uptake and accumulation is cytotoxic and can lead to lipoapoptosis: lipoptosis.

21173 Background: Pancreatic malignancies belong to the top-five killers among all cancers worldwide. The 5-year survival rate with conventional therapy is below 5%. This shows that there is a big need for new therapeutical approaches. The fully human monoclonal antibody SAM-6 is a germ-line coded IgM, isolated from a cancer patient by TRIOMA technology. SAM-6 antibody binds to a modified O-linked carbohydrate moiety expressed on a membrane-bound variant of GRP78, which is a member of the HSP70 family. Heat-shock proteins (HSPs) are critical components of a cell's defense mechanism against injury associated with adverse stresses. They can protect cells against subsequent, otherwise lethal, outcome. Although HSPs are very beneficial to the normal cell, cancer cells often over-express HSPs on the membrane. They use them in response to stresses associated with various therapies, diminishing the treatment effects. Methods: In vitro and in vivo assays were used to investigate the apoptotic effects of antibody SAM-6 on pancreas cancer cells. Results: Binding of SAM-6 antibody to GRP78 induces an overfeeding of malignant cells with oxidized LDL. The cancer cells over-accumulate depots of cholesterol and triglyceride esters and finally undergo apoptosis. The deadly effect of SAM-6 could be demonstrated in vitro and in vivo in experimental animal models. Conclusions: These data show that cancer-specific modifications of cell surface protection molecules are ideal targets for immuno-therapeutical approaches. No significant financial relationships to disclose.