Specific activation of resting T cells against tumour cells by bispecific antibodies and CD28‐mediated costimulation is accompanied by Th1 differentiation and recruitment of MHC‐independent cytotoxicity
Specific activation of resting lymphocytes for tumour targeting can be achieved by bispecific monoclonal antibodies (bi‐MoAbs) with specificity for tumour antigens and T cell‐activating antigens in combination with a costimulatory anti‐CD28 antibody. In this study we focus on the immunomodulatory function of an anti‐CD3/CA19‐9 bi‐MoAb in combination with a costimulatory anti‐CD28 antibody which may result not only in antigen‐specific, T cell‐mediated tumour cell lysis but also in recruitment of other cellular effector functions. In combination with costimulatory anti‐CD28 antibodies, resting peripheral lymphocytes could be activated specifically to secrete high amounts of Th1 cytokines (IL‐2, interferon‐gamma (IFN‐γ)) characterizing a cellular immune response. In contrast, no IL‐4 and only low amounts of IL‐10 could be detected. Furthermore, bi‐MoAb‐mediated CA19‐9‐specific activation of T cells was accompanied by recruitment of MHC‐ and CA19‐9‐independent cytotoxicity, as was determined by lysis of different CA19‐9−cell lines. This MHC‐independent cytotxicity was mediated at least in part by activated natural killer (NK) cells, as depletion of CD16+ NK cells resulted in substantial decrease of cytotoxicity against CA19‐9− targets. Our results indicate that specific activation of resting T cells with CD3‐associated bi‐MoAbs in combination with an anti‐CD28 antibody leads to a Th1 differentiation pathway and is accompanied by recruitment of MHC‐independent lymphokine‐activated killer (LAK) cell cytotoxicity which can possibly be directed against a heterogeneous tumour.