Despite the recent development of novel therapies for patients with metastatic melanoma, this disease remains fatal in the majority of those who develop a relapse. Here, we report the preclinical and early clinical development of a novel IgM antibody PAT-SM6 that specifically binds to a cancer-specific isoform of glucose-regulated protein 78 (GRP78) and low-density lipoprotein. Finding a GRP78 cancer-specific form on the surface of cancer cells, but not normal cells in vivo, presents an opportunity for cancer-specific targeting. PAT-SM6 binding to the cell surface induces apoptosis in a variety of tumors, including melanoma. Recent studies show the specificity of PAT-SM6 binding to the surface of melanoma cells and primary tissue but not to normal tissue. They also confirm, for the first time, cell proliferation inhibition and apoptosis through classical apoptotic pathways as well as induction of lipid accumulation in melanoma cells. These in-vitro data are supported by positive in-vivo data using PAT-SM6 in a xenograft C8161 model. Furthermore, PAT-SM6 was well tolerated in pharmacokinetic/toxicology studies in monkeys. On the basis of these preclinical observations, a clinical study of PAT-SM6 was carried out in patients with 'in-transit' melanoma. Even with microdosing, histological analyses of tumor biopsies detected the presence of PAT-SM6 as well as apoptosis. Although there are many small molecules and monoclonal antibodies currently in clinical development for patients with melanoma, PAT-SM6 is the only therapeutic targeting the cancer-specific isoform of GRP78. These PAT-SM6 preclinical data and positive findings from the phase 1 safety study provide strong support for the further development of this novel antibody.