Effect of Antigenic Heterogeneity on the Efficacy of Enhanced Delivery of Antibody-targeted Chemotherapy in A Human Lung Cancer Intracerebral Xenograft Model in Rats

OBJECTIVE: The SGN-15 monoclonal antibody-doxorubicin immunoconjugate is toxic to Lewis^Y antigen-expressing cells and is effective against intracerebral tumors in nude rats when delivery is enhanced with osmotic disruption of the blood-brain barrier (BBB). We tested whether doxorubicin released locally in antigen-expressing cells would affect adjacent non-antigen-expressing cells in heterogeneously expressing intracerebral tumors. METHODS: Nude rats with intracerebral xenografts of human small cell lung carcinoma cells with high (n = 10) or low (n = 23) Lewis^Y antigen expression were treated with SGN-15 at a low (10 mg/kg) or high (140 mg/kg) antibody dose, administered intra-arterially with BBB disruption, and tumor volumes and antigen expression were evaluated after 6 days. RESULTS: BBB disruption-enhanced delivery of SGN-15 (10 mg/kg) reduced the high-expressor tumor volume from 26.1 ± 3.7 mm³ (n = 7) in untreated control animals to 6.7 ± 4.6 mm³ (n = 3, P < 0.05). Untreated high-expressor tumors exhibited uniform prominent Lewis^Y antigen staining (97.6 ± 0.9% positive, n = 4), whereas treated tumors demonstrated areas of nil, moderate, and prominent staining (71.0 ± 8.5% positive, n = 3, P < 0.05). In intracerebral tumors with low initial antigen expression, BBB disruption-enhanced delivery of a low dose of immunoconjugate was significantly effective, but treated tumors demonstrated low levels of antigen expression. An increase in the immunoconjugate dose did not significantly alter either efficacy or antigen expression. CONCLUSION: Immunoconjugate delivered across the BBB was effective against antigen-positive tumor cells, but there was not an effective chemical bystander effect against antigen-negative tumor cells.