ANTI-HER2 IMMUNOLIPOSOMES FOR TARGETED THERAPY OF HUMAN TUMORS

Anti-HER2 immunoliposomes (ILs) have been constructed by conjugation o f Fab' fragments of recombinant humanized monoclonal antibody rhuMAbHE R2 to small sterically stabilized unilamellar liposomes, to create a t argeted drug delivery vehicle for the treatment of HER2 (c-erbB-2, neu )-overexpressing cancers. Parameters affecting in vitro binding and in ternalization of ns include liposome composition, Fab' linkage site an d Fab' density. Anti-HER2 ns have been constructed to optimize intrace llular drug delivery. Doxorubicin (dox)-loaded ILs are highly stable a nd exhibit prolonged circulation in rats. In nude mice bearing HER2-ov erexpressing tumor xenografts, anti-HER2 ILs administered i.v. resulte d in efficient tumor localization, with penetration of the ILs through out the tumor mass and accumulation within tumor cells. In contrast, n ontargeted liposomes resulted in extracellular tumor accumulation only . In multiple HER2-overexpressing human breast tumor xenograft models, treatment with dox-loaded anti-HER? ILs produces significantly increa sed antitumor cytotoxicity as compared to free dox or dox-loaded non-t argeted liposomes and significantly less systemic toxicity than free d ox. To explore further the intracellular delivery advantages of ILs, a nti-HER2 ILs bearing cationic lipids are being developed for nucleic a cid delivery. These cationic immunoliposomes mediate efficient and spe cific transfection of target cells with reporter genes, as well as int racellular delivery of labeled oligonucleotides. Thus, anti-HER2 ILs r epresent an efficient and feasible strategy to achieve targeted intrac ellular delivery of therapeutic agents. (C) 1997 Elsevier Science Irel and Ltd.