TARGETING OF HUMAN AND MOUSE T-LYMPHOCYTES BY MONOCLONAL-ANTIBODY HPMA COPOLYMER DOXORUBICIN CONJUGATES DIRECTED AGAINST DIFFERENT T-CELL SURFACE-ANTIGENS

Binding of HPMA copolymer-conjugated doxorubicin targeted with monoclo nal antibodies directed against various T-cell surface receptors, i.e. Thy1.2 (CDw90), I-A (MHC class II. glycoprotein), L3T4 (CD4), IL-2R ( CD25) and CD3, is considerably increased in Con A stimulated T-lymphoc ytes. FACS analysis showed that the binding is most intensive with ant i-Thy1.2 and anti-L3T4 targeted derivatives and it is proportional to the antiproliferative effect of the antibody-targeted drug. No binding and no antiproliferative capacity was observed after in vitro incubat ion of mouse T-cells with a nonspecific mouse IgG-HPMA-DOX conjugate. [H-3]-TdR incorporation was inhibited considerably more in Con A stimu lated T-cell culture and in EL4 mouse T-cell lymphoma as compared with the culture of nonactivated T-lymphocytes. This proves that intensive ly proliferating cells are more susceptible to the inhibitory action o f an antibody-targeted drug. The cytotoxic efficacy of HPMA copolymer with GlyPheLeuGly or GlyLeuPheGly side-chains to which the drug is con jugated was superior to HPMA copolymer with GlyPheGly or GlyLeuGly sid e-chains. However, there is no direct correlation between the rate of in vitro drug release and the in vitro cytotoxicity of the respective conjugates. This suggests that the rate of drug release from the conju gate is only one factor responsible for the pharmacological efficacy o f the preparation. Furthermore, we detected substantial and prolonged inhibition of proliferation of Con A activated T-cells only if doxorub icin was injected in vivo in the form of an anti-Thy1.2-targeted conju gate. (C) 1998 Elsevier Science B.V.