IMMUNOSUPPRESSION OF GRAFT REJECTION WITH IDARUBICIN-MONOCLONAL ANTIBODY CONJUGATES BY ELIMINATION OF T CELL SUBSETS IN VIVO

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Abstract
Idarubicin, a more therapeutically effective derivative of daunomycin, when coupled to monoclonal antibodies that react with murine and human tumors has the ability to specifically target and eradicate tumor cell populations in vitro and in vivo. In this study the in vitro and in vivo efficacy of idarubicin coupled to monoclonal antibodies reactive with distinct subpopulations of lymphocytes (L3T4+, Ly-2+) has been characterized. Using a tumor allograft model in vivo the potential use of drug-monoclonal antibody conjugates to prevent graft rejection has been investigated. Three to five molecules of Idarubicin could be coupled to the monoclonal antibodies (anti-Ly-2.1, anti-L3T4, or anti-Thy-1) with retention of protein solubility and antibody activity. Some loss of idarubicin activity (4–10-fold) occurred upon conjugation to the monoclonal antibodies—however, selective cytotoxicity for antibody reactive cell lines was observed. All three conjugates demonstrated the capacity to significantly deplete reactive subsets of spleen cells—further evidenced by the ability of combined idarubicin-anti-L3T4 and Idarubicin-anti-Ly-2.1 treatment of idarubicin-anti-Thy-1 treatment to prolong the survival of (Ly-2−, L3T4−) P388D1 tumor grafts in CBA mice in the presence of H-2 and non H-2 antigenic differences. This form of selective immunosuppression may have relevance for the treatment of graft rejection in man.