TNFalpha contributes to the antitumor activity of a bispecific, trifunctional antibody.

Immunological cancer therapies focus on the activation of immune effector cells yielding a specific antitumor activity. Disseminated tumor cells are regarded as the origin of metastases and consequently their elimination is the central objective of adjuvant immune therapies. The use of bispecific antibodies is an approach that is regarded as promising in order to fight those disseminated tumor cells. Unfortunately, the efficiency of these antibodies is limited by the fact that they usually activate a single class of effector cell, thus not yielding optimal immune response. In addition, tumor cells may down-regulate the antibody's target molecule and escape recognition. We have recently described results with an intact bispecific molecule, BiUII, that represents a new class of intact antibodies. These antibodies, termed "triomab", provide an excellent antitumor activity in vitro, a fact that most probably is attributable to the simultaneous activation of different classes of immune effector cells. We have now investigated this antitumor activity in more detail and demonstrate here that at least a dual mechanism accounts for triomab-mediated killing of tumor cells: besides direct cell-mediated killing, triomab induces the production of TNFalpha in PBMCs at concentrations that induce apoptosis in target cells. This bystander effect may be of special interest for the clinical application of triomab in terms of killing of target antigen-negative tumor cells.