Natural IgM antibodies as therapeutic tools for epithelial cancer
F. Hensel; OncoMab GmbH, Friedrich-Bergius-Ring 15, D-97076 Würzburg, Germany.

S. Brändlein, H.K. Müller-Hermelink, & H.P. Vollmers; Institute of Pathology, University of Würzburg, Josef-Schneider-Straße 2, D-97080 Würzburg, Germany.

Malignancy is like a chronic disease, and the immune system is permanently engaged in detecting and eliminating the constantly emerging transformed cells. The human hybridoma technology offers the unique opportunity to study the mechanisms, structures, and targets involved in recognition and elimination of aberrant cells.

Thousands of tumor-reactive human monoclonal antibodies were isolated directly from cancer patients and from healthy donors by the human hybridoma technique. Without exception the isolated antibodies were of IgM isotype; no IgG or IgA antibodies were found. The most interesting antibody candidates were selected for DNA sequence analysis, characterization of their binding patterns, and determination of their origin and genetics. All of the IgM antibodies studied so far express only few or no mutations at all and thus are germ-line encoded. They bind to carbohydrates on modified tumor-specific receptors and induce apoptosis of tumor cells. Interestingly, the degree of cross-reactivity to other tumors correlates reciprocally with the number of mutations in the coding regions.

These data indicate that innate immunity and natural IgM antibodies play an important role in immunosurveillance mechanisms against epithelial tumors in humans. Oncomab uses this potential to generate fully human anti-cancer drugs which are effective in cancer patients. The success of this principle was already shown by the IgM type antibody SC-1. This human antibody is targeting a specific isoform of CD55 present in about 60% of stomach carcinomas. In a prospective study, the antibody was administered prior to surgery in 51 patients and was shown to specifically induce tumor apoptosis and tumor regression.