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

The product of the HER2 protooncogene, p185(HER2), represents an attractive target for cancer immunotherapies. We have prepared anti-p185(HER2) immunoliposomes in which Fab' fragments of a humanized anti-p185(HER2) monoclonal antibody with antiproliferative properties (rhuMAbHER2) were conjugated to either conventional or sterically stabilized liposomes. These immunoliposomes bind specifically to p185(HER2)-overexpressing breast cancer cells (SK-BR-3 and BT-474). High-affinity binding of anti-p185(HER2) immunoliposomes is comparable to that of free rhuMAbHER2-Fab' or the intact antibody, Empty immunoliposomes inhibit the culture growth of p185(HER2)-overexpressing breast cancer cells, and this antiproliferative effect is superior to that of free rhuMAbHER2-Fab', indicating that liposomal anchoring of these anti-p185(HER2) Fab' fragments enhances their biological activity. Efficient internalization of anti-p185(HER2) immunoliposomes, demonstrated by light and electron microscopy, occurs by receptor-mediated endocytosis via the coated pit pathway and also possibly by membrane fusion. Doxorubicin-loaded anti-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 breast 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 human cancers.