Induction of immune responses against metastatic disease is the most challenging strategy in cancer vaccine development. Tumor cells, however, escape an ongoing immune response using various mechanisms including loss of target antigen and down regulation of MHC molecules or disruption of complement cascade. Therefore, employing novel anti-tumor immunological mechanisms in the immunotherapy array are needed. Induction of humoral responses that mediate apoptosis is perceived to be beneficial in vaccine formulations. Some plant lectins like Griffonia simplicifolia lectin I (GS-I) and wheat germ agglutinin (WGA) mediate apoptosis of tumor cells. We hypothesize that using these lectins as a template to select peptide mimotopes enables us to develop mimotope vaccines capable of inducing carbohydrate cross-reactive apoptotic antibodies upon immunization. We selected a peptide mimotope based on its specific reactivity with the above-mentioned lectins. Immunization of animals with the selected mimotope induced serum IgM antibodies that bound to murine 4T1 and human MCF7 cell lines as assayed by flow cytometry. Serum antibodies mediated apoptosis in both cell lines as assayed by annexin V surface expression, paralleling the apoptotic activity of the lectins. Confocal microscopy demonstrated that serum IgM antibodies internalized after co-incubation with the cells. Using 4T1 as a spontaneous metastatic tumor model, we observed that immunization of tumor-bearing animals with the mimotope significantly increased the survival time that was attributed to an observed diminished metastatic ratio of the tumor cells colonizing the liver. In prophylactic immunization of naive mice, we found that the vaccine is able to also affect solid tumor and lung metastasis. This finding parallels suggestions that carbohydrate reactive IgM can function as apoptotic mediators of tumor cell. Therefore, induction of apoptotic IgM antibodies might be targeted as an end-point in the development of vaccination strategies against cancer especially in the adjuvant setting for metastatic disease.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]