IL-2 receptor-targeted cytolytic IL-2/Fc fusion protein treatment blocks diabetogenic autoimmunity in nonobese diabetic mice

High affinity IL-2R(5) is present on recently activated but not on resting or memory T cells. Selective targeting of T cells bearing high affinity IL- 2R is an attractive therapy for many T cell-dependent cytopathic disease pr ocesses, A variety of rodent mAbs directed against the alpha-chain of the I L-2R, as well as IL-2 fusion toxins, have been used in animals and humans t o achieve selective immunosuppression, Here we report on the development of a novel IL-2R targeting agent, a cytolytic chimeric IL-2/Fc fusion protein . This immunoligand binds specifically and with high affinity to IL-2R and is structurally capable of recruiting host Ab-dependent cell-mediated cytot oxicity and complement-dependent cytotoxicity activities. The Ig component ensures an extended circulating t(1/2) of 25 h following systemic administr ation. To subsequently explore the mechanisms of the antidiabetogenic effec ts of IL-2/Fc, we have mutated the FcR binding and complement C1q binding ( Fc(-/-)) domains of the Fc fragment to render the Fc unable to direct Ab-de pendent cell-mediated cytotoxicity and complement-dependent cytotoxicity ac tivities. In a model of passive transfer of diabetes in nonobese diabetic m ice, lytic IL-2/Fc, but not nonlytic IL-2/Fc(-/-), exhibited striking antid iabetogenic effects. Together with the negligible potential of IL-2/Fc for immunogenicity, this finding forecasts that cytolytic IL-2/Fc may offer a n ew therapeutic approach for selective targeting of auto and alloimmune T ce lls.