T10B9 (MEDI-500) MEDIATED IMMUNOSUPPRESSION - STUDIES ON THE MECHANISM OF ACTION

The murine IgM anti-human CD3/TCR mAb T10B9 is an effective agent for the reversal of acute cellular renal allograft rejection which offers several advantages over conventional OKT3 therapy. These include reduc ed morbidity and a more rapid decrease in serum creatinine levels. In the studies presented here comparing T10B9 and OKT3, soluble T10B9 is shown to be a nonactivating anti-T cell mAb, Evidence for its lack of activating potential includes in vitro failure to stimulate PBMC proli feration either alone or in the presence of nonmitogenic doses of phor bol ester, failure to induce the expression of early and late activati on antigens and failure to induce IFN-gamma, TNF-alpha, IL-6 or IL-2 r elease. Analysis of acute renal allograft rejection patient plasma cyt okine levels 2 h after the first dose support the hypothesis that T10B 9 has reduced immunoactivation activity in vivo. Both TNF alpha and IF N gamma patient plasma levels are significantly reduced in T10B9 as co mpared to OKT3 therapy. However, T10B9 is capable of cellular signalin g as demonstrated by its ability to induce apoptosis and IL-2 release in the human T cell line Sup-T13. Thus T10B9 retains the potent immuno suppressive activity of OKT3 with reduced immunoactivation.