Enhanced delivery improves the efficacy of a tumor-specific doxorubicin immunoconjugate in a human brain tumor xenograft model

OBJECTIVE: To evaluate dose intensification with osmotic blood-brain barrie r disruption (BBBD) and the potential use of drug targeting with monoclonal antibody (MAb) BR96 conjugated to doxorubicin (BR96-DOX, now called SGN15) for treatment of intracerebral and subcutaneous human LX-1 small cell lung carcinoma xenografts in rats. METHODS: LX-1 tumors with high, low, or heterogeneous levels of the Lewis(y ) antigen for BR96 were evaluated. Rats were treated with intracarotid or i ntravenous BR96-DOX, with or without osmotic BBBD. RESULTS: Both BR96-DOX acid MAb BR96 treatment resulted in significant regr ession of subcutaneous tumors, in contrast to control groups including doxo rubicin alone, saline, or nonbinding doxorubicin immunoconjugate. BR96-DOX delivered with BBBD to brain tumors with low antigen expression resulted in significantly (P < 0.001) increased rat survival time compared with animal s that received intravenous or intra-arterial BR96-DOX. CONCLUSION: The combination of an effective drug such as doxorubicin with a MAb to facilitate tumor-selective localization and osmotic BBBD to increas e tumor delivery may have practical application in the clinic, because an i ncreased delivery of drug to tumor can be obtained without increasing the d ose of systemic drug.