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

To overcome dose limiting toxicities and to increase efficacy of immunother apy of cancer, a number of strategies are under development for selectively redirecting effector cells/molecules towards tumor cells. Many of these st rategies exploit the specificity of tumor associated antigen recognition by monoclonal antibodies. Using either hybridoma fusion, chemical derivatizat ion or molecular biology technology, antibodies with dual specificity can b e constructed. These so called bispecific antibodies (BsAbs) have been used to redirect the cytolytic activity of a variety of immune effector cells s uch as cytotoxic T lymphocytes, natural killer cells, neutrophils and monoc ytes/macrophages to tumor cells. Local administration of BsAbs, either alon e or in combination with autologous effector cells, is highly effective in eradicating tumor cells. In contrast, systemic application of BsAb at prese nt is only suitable for adjuvant treatment of minimal residual disease due to poor tumor cell accessibility. As an alternative, angiogenesis related d eterminants on tumor blood vessels can be exploited for the selective deliv ery of effector cells/molecules apart from being used to inhibit angiogenes is. Important advantages of this strategy is that the endothelial cell asso ciated target epitope(s) are easy accessible. The dependence of tumor growt h on the tumor's blood supply also renders tumor endothelial cells an attra ctive target for therapy. Although still in its infancy, attacking the tumo r's blood supply for example by delivering immunotherapies holds great prom ise for antineoplastic therapy. coagulation factors or toxins, or by BsAb d irected (C) 2000 Elsevier Science B.V. All rights reserved.