MCC-465 is an immunoliposome-encapsulated doxorubicin (DXR). The liposome is tagged with polyethylene glycol and the F(ab’)2 fragments of a monoclonal antibody named GAH, a human antibody obtained by the hybridoma technique. The epitope recognized by GAH is not well characterized, but most of human gastric, colorectal, and mammary cancer cell lines are GAH-positive, while the normal counterparts are GAH-negative. The staining in carcinoma cell lines occurs mostly on the cell membrane and /or as a diffuse cytoplasmic staining. In vitro, MCC-465 bounds to the GAH-reactive cells and internalized. We examined GAH-positivity immunohistochemically on formalin-fixed, paraffin-embedded gastrointestinal cancer surgical specimens and observed high positivities (around 90%). Thus, GAH-conjugated immunoliposomes were thought to be highly potent as a drug-targeting device for cancer therapy. We previously showed that anti-tumor effect of MCC-465 was significantly superior against GAH-positive colon cancer xenografts compared with pegylated liposomal doxorubicin (PLD). One of PLD, Doxil® is now recommended as a second-line treatment for advanced ovarian cancer patients who are initially resistant or refractory to first-line platinum-based combination therapy or has become resistant after successive cycles of platinum combination therapy. In the present study, we examined GAH-positivity on ovarian cancer surgical specimens to seek the possibility of MCC-465 as a drug for ovarian cancer therapy. Immmunostaining was performed on sixty-five archival paraffin-embedded tissue blocks of ovarian cancer patients treated in 1996-2000 and we observed 91% of the specimens were GAH-positive according to our criteria. Cytotoxicity assay against ovarian carcinoma cell lines showed superior activity of MCC-465 compared to PLD. Confocal microscopy of subcellular distribution of MCC-465 and PLD in vitro revealed that DXR encapsulated in MCC-465 quickly localized in the nuclei of GAH-positive ovarian carcinoma cell lines, whereas PLD seemed to distribute only in cytoplasm. These results suggest that MCC-465 will be more beneficial compared to PLD not only with respect to targeting cancerous tissues, but also favorable subcellular distributions of cancer cells.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]