Antibody therapeutic approaches for cancer

Abstract

FcalphaRI as target for antibody therapy: Anti-tumor antibodies are promising therapeutics for cancer. Currently, all FDA-approved therapeutic antibodies are of the IgG class, which interact with IgG receptors (FcgammaR). In this project we examined the role of the IgA Fc receptor, FcalphaRI (CD89) in antibody therapy. Antibody-induced neutrophil migration was studied in 3-dimensional collagen culture assays, in which tumor-colonies were grown. Minimal tumor-directed neutrophil migration was induced by IgG anti-tumor antibodies. In contrast, FcalphaRI triggered massive neutrophil migration and tumor-colony destruction. Production of chemotactic factors and release of inflammatory cytokines were increased, as well, suggesting an FcalphaRI-induced autocrine loop, leading to neutrophil migration and consequent destruction of tumor-colonies. In addition, tumor-cell killing was consistently more effective via triggering of FcalphaRI, than via FcgammaRI. Taken together, neutrophil FcalphaRI might represent an effective target for antibody therapy. Successful antibody therapy against liver-metastases: In colorectal cancer, many patients will develop liver-metastases, even after successful surgical removal of the primary tumor at a time at which no visible metastases are present. Peri-operative adjuvant treatment might, therefore, help to prevent secondary disease. We studied the potential of antibody-therapy to prevent outgrowth of liver-metastases in mice. Peri-operative treatment with anti-gp75 IgG2a prevented outgrowth of B16F10 liver-metastases in more than 90% of mice. Therapeutic efficacy was maintained in either C1q-, or CR3-deficient mice, but was abrogated in FcRgamma chain-deficient mice, which lack all activatory FcgammaR. These results indicate that interactions with activatory FcgammaR are necessary for successful antibody therapy of cancer. Because antibody therapy was still effective in FcgammaRI-/-, FcgammaRIII-/- and FcgammaRI/III-/- mice, an important role for the newly identified FcgammaRIV is supported.