Target cell-restricted triggering of the CD95 (APO-1/Fas) death receptor with bispecific antibody fragments

Like many other cell surface receptors, the CD95 (APO-1/Fas) molecule needs to be cross-linked by its physiological ligand or by immobilized or multim eric antibodies to mediate biological activity, that is, induction of apopt otic cell death. Monomeric CD95 antibodies of the IgG2a or IgG1 subtype blo ck rather than induce apoptosis, We report here that such antibodies, hybri dized to a second antibody directed against a different target antigen on t he same cell, effectively induce apoptosis of the cells if the expression o f the target antigen exceeds a certain threshold level. It appears that thi s effect is due to bicellular binding of bispecific antibodies: resulting i n mutual cross-linking of the CD95 death receptor and the target antigen, U sing bispecific reagents, it may therefore be possible to restrict the acti vation of death receptors to a given target site, e.g, a tumor. In general terms, our findings illustrate a principle according to which the triggerin g of a cell surface receptor may be confined to a given target cell using b ispecific reagents with target X cell surface receptor specificity.