Development of anti-p185HER2 immunoliposomes for cancer therapy.
The product of the HER2 protooncogene, p185HER2, represents an attractive target for cancer immunotherapies. We have prepared anti-p185HER2 immunoliposomes in which Fab' fragments of a humanized anti-p185HER2 monoclonal antibody with antiproliferative properties (rhuMAb-HER2) were conjugated to either conventional or sterically stabilized liposomes. These immunoliposomes bind specifically to p185HER2-overexpressing breast cancer cells (SK-BR-3 and BT-474). High-affinity binding of anti-p185HER2 immunoliposomes is comparable to that of free rhuMAbHER2-Fab' or the intact antibody. Empty immunoliposomes inhibit the culture growth of p185HER2-overexpressing breast cancer cells, and this antiproliferative effect is superior to that of free rhuMAbHER2-Fab', indicating that liposomal anchoring of these anti-p185HER2 Fab' fragments enhances their biological activity. Efficient internalization of anti-p185HER2 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-p185HER2 immunoliposomes are markedly and specifically cytotoxic against p185HER2-overexpressing tumor cells in vitro. Anti-p185HER2 immunoliposomes administered in vivo in Scid mice bearing human breast tumor (BT-474) xenografts can deliver doxorubicin to tumors. These results indicate that anti-p185HER2 immunoliposomes are a promising therapeutic vehicle for the treatment of p185HER2-overexpressing human cancers.
Park
J W
JW
Department of Medicine, University of California, San Francisco 94143.
Hong
K
K
Carter
P
P
Asgari
H
H
Guo
L Y
LY
Keller
G A
GA
Wirth
C
C
Shalaby
R
R
Kotts
C
C
Wood
W I
WI
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000633:toxicity; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D004705:Endocytosis; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage; D006801:Humans; D066298:In Vitro Techniques; D008081:Liposomes / Q000493:pharmacokinetics; D051379:Mice; D016513:Mice, SCID; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D004317:Doxorubicin; D006131:Growth Inhibitors; D008081:Liposomes; D018719:Erb-b2 Receptor Tyrosine Kinases