Bispecific antibodies for treatment of cancer in experimental animal models and man

Immunotherapy is a powerful anti-cancer treatment modality. However, despite numerous encouraging results obtained in pre-clinical studies, a definite breakthrough towards an established clinical treatment modality has as yet not occurred. Antibodies against tumor antigens have been shown to localise at the site of the tumor, but inadequate triggering 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 complex (MHC)-expression or Fas ligand up-regulation on tumor cells. This review focuses on the use of bispecific antibodies (BsAbs) for immunotherapy of cancer. Using BsAbs, it is possible to take advantage of the highly specific binding characteristics of antibodies and combine these with the powerful effector functions of cytotoxic immune effector cells. BsAbs share two different, monoclonal antibody-derived, antigen-recognizing moieties within one molecule. By dual binding, BsAbs reactive 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 able 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 preclinical models and in a number of phase I clinical trials. Promising pre-clinical results have been reported using tumor models in which diverse 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 preclinical models that have led to the current use of BsAbs in experimental clinical trials. It has become clear that appropriate immune cell activation and establishing a favourable effector-to-target cell ratio will have direct impact on the efficacy of the therapeutic approaches using BsAbs. New directions are discussed, i.e. finding appropriate dosage schemes by which immune effector cells become redirected without inducing hyporesponsiveness, defining possibilities for combining different immune effector cell populations and creating an in situ tumor environment that allows maximal tumoricidal activity