DEVELOPMENT OF ANTI-P185(HER2) IMMUNOLIPOSOMES FOR CANCER-THERAPY

The product of the HER2 protooncogene, p185(HER2), represents an attra ctive target for cancer immunotherapies. We have prepared anti-p185(HE R2) immunoliposomes in which Fab' fragments of a humanized anti-p185(H ER2) monoclonal antibody with antiproliferative properties (rhuMAbHER2 ) were conjugated to either conventional or sterically stabilized lipo somes. These immunoliposomes bind specifically to p185(HER2)-overexpre ssing breast cancer cells (SK-BR-3 and BT-474). High-affinity binding of anti-p185(HER2) immunoliposomes is comparable to that of free rhuMA bHER2-Fab' or the intact antibody, Empty immunoliposomes inhibit the c ulture growth of p185(HER2)-overexpressing breast cancer cells, and th is antiproliferative effect is superior to that of free rhuMAbHER2-Fab ', indicating that liposomal anchoring of these anti-p185(HER2) Fab' f ragments enhances their biological activity. Efficient internalization of anti-p185(HER2) immunoliposomes, demonstrated by light and electro n microscopy, occurs by receptor-mediated endocytosis via the coated p it pathway and also possibly by membrane fusion. Doxorubicin-loaded an ti-p185(HER2) immunoliposomes are markedly and specifically cytotoxic against p185(HER2)-overexpressing tumor cells in vitro. Anti-p185(HER2 ) immunoliposomes administered in vivo in Scid mice bearing human brea st tumor (BT-474) xenografts can deliver doxorubicin to tumors. These results indicate that anti-p185(HER2) immunoliposomes are a promising therapeutic vehicle for the treatment of p185(HER2) overexpressing hum an cancers.