Experimental treatment of malignant gliomas with human monoclonal antibody-drug conjugates

This study was designed to determine whether the monoclonal antibody-drug c onjugates are more potent than the free drugs in killing human glioma cells in vitro and in vivo. The anticancer drugs doxorubicin (DXR) and 4'-epi-do xorubicin (epi-DXR) were separately conjugated to the human monoclonal anti body (mAb) CLNIgG, which binds strongly to human malignant glioma cells. Th e cytotoxic activity of the mAb-drug conjugates was assessed by a H-3-thymi dine assay in vitro. The efficacy, biodistribution and autography of the im munoconuugates were examined using the subcutaneous glioma model (nude mous e). The epi-DXR-CLNIgG conjugate was found to be 11 times more potent than free epi-DXR in killing glioma cell sin vitro, and epi-DXR-CLNIgG clearly a chieved the mot favorable antitumor effects. A biodistribution study using [14-C-14]DXR-CLNIgG at the conjugate indicated that the immunoconjugates de livered DXR to glioma tissues at least five times more than the free DXR al one in nude mice without increasing the concentration in other tissues. An autoradiographic study also showed good accumulation of the antibody-drug c onjugate in the subcutaneously transplanted glioma. Thus the human monoclon al antibody-drug conjugates constitute a potential new approach for the tre atment of malignant gliomas.