Human monoclonal antibody-drug conjugates in the experimental treatment of malignant gliomas--studies in vitro and in vivo.

The chemotherapeutic agents doxorubicin (DXR) and 4'-epi-doxorubicin were separately conjugated to the human monoclonal antibody CLNIgG, which binds strongly to human malignant glioma cells. The antibody-drug conjugates were more potent than the free drugs in killing human glioma cells in vitro and in vivo (subcutaneous glioma model). A biodistribution study using [14-14C]DXR-CLNIgG conjugate indicated that immunoconjugates delivered at least five times more DXR to glioma tissues than free DXR alone in nude mice without increasing the concentration in other tissues. In a nude rat intracerebral glioma model, intracarotid hyperosmolar perfusion to achieve blood-brain barrier (BBB) opening caused a 640% increase in the DXR-CLNIgG concentration in intracerebral tumor tissue. Human monoclonal antibody-drug conjugates in combination with BBB opening is a potential new approach to the treatment of malignant gliomas.