BISPECIFIC ANTIBODIES FOR TREATMENT OF CANCER IN EXPERIMENTAL ANIMAL-MODELS AND MAN

Immunotherapy is a powerful anti-cancer treatment modality. However, d espite numerous encouraging results obtained in pre-clinical studies, a definite breakthrough towards an established clinical treatment moda lity has as yet not occurred. Antibodies against tumor antigens have b een shown to localise at the site of the tumor, but inadequate trigger ing of immune effector mechanisms have thwarted clinical efficacy thus far. Cellular immunotherapy has been hampered by limitations such as lack of specificity, down-regulation of major histocompatibility compl ex (MHC)-expression or Fas ligand up-regulation on tumor cells. This r eview focuses on the use of bispecific antibodies (BsAbs) for immunoth erapy of cancer. Using BsAbs, it is possible to take advantage of the highly specific binding characteristics of antibodies and combine thes e with the powerful effector functions of cytotoxic immune effector ce lls. BsAbs share two different, monoclonal antibody-derived, antigen-r ecognizing moieties within one molecule. By dual binding, BsAbs reacti ve with a trigger molecule on an immune effector cell on the one hand and a surface antigen on a tumor target cell on the other are thus abl e to functionally focus the lytic activity of the immune effector cell towards the target cell. Over the last few years, the concept of BsAb -mediated tumor cell killing has been studied extensively both in prec linical models and in a number of phase I clinical trials. Promising p re-clinical results have been reported using tumor models in which div erse immune effector cell populations have been used. Despite this pre -clinical in vivo efficacy, the first clinical trials indicate that we are still not in a position to successfully treat human malignancies. This review discusses the production of BsAbs, the choice of trigger molecules in combination with potential effector cells and the preclin ical models that have led to the current use of BsAbs in experimental clinical trials. It has become clear that appropriate immune cell acti vation and establishing a favourable effector-to-target cell ratio wil l have direct impact on the efficacy of the therapeutic approaches usi ng BsAbs. New directions are discussed, i.e. finding appropriate dosag e schemes by which immune effector cells become redirected without ind ucing hyporesponsiveness, defining possibilities for combining differe nt immune effector cell populations and creating an in situ tumor envi ronment that allows maximal tumoricidal activity. (C) 1998 Elsevier Sc ience B.V.