The use of bispecific antibodies in tumor cell and tumor vasculature directed immunotherapy.

To overcome dose limiting toxicities and to increase efficacy of immunotherapy of cancer, a number of strategies are under development for selectively redirecting effector cells/molecules towards tumor cells. Many of these strategies exploit the specificity of tumor associated antigen recognition by monoclonal antibodies. Using either hybridoma fusion, chemical derivatization or molecular biology technology, antibodies with dual specificity can be constructed. These so called biospecific antibodies (BsAbs) have been used to redirect the cytolytic activity of a variety of immune effector cells such as cytotoxic T lymphocytes, natural killer cells, neutrophils and monocytes/macrophages to tumor cells. Local administration of BsAbs, either alone or in combination with autologous effector cells, is highly effective in eradicating tumor cells. In contrast, systemic application of BsAb at present is only suitable for adjuvant treatment of minimal residual disease due to poor tumor cell accessibility. As an alternative, angiogenesis related determinants on tumor blood vessels can be exploited for the selective delivery of effector cells/molecules apart from being used to inhibit angiogenesis. Important advantages of this strategy is that the endothelial cell associated target epitope(s) are easy accessible. The dependence of tumor growth on the tumor's blood supply also renders tumor endothelial cells an attractive target for therapy. Although still in its infancy, attacking the tumor's blood supply for example by delivering coagulation factors or toxins, or by BsAb directed immunotherapies holds great promise for antineoplastic therapy.