Efficacy of immunoliposomes on cancer models in a cell-surface-antigen-density-dependent manner.
We have recently established a cancer-reactive human monoclonal antibody, GAH, with a positive ratio of over 90% against stomach cancer. GAH was formulated as polyethyleneglycol (PEG)-modified immunoliposomal doxorubicin (DXR) (ILD) and its efficacy was examined against gastrointestinal human cancers. In in vitro studies, a comparison of ILD with PEG-modified liposomal DXR (LD) demonstrated that ILD had dose-dependent cytotoxicity for GAH-reactive B37 cancer cells, but not LD. In concordance with this result, microscopic observations showed that ILD was bound to and GAH-dependently internalised by B37 cells. In in vivo studies, ILD exhibited significantly greater antitumour activity on cancer xenograft models than LD or free DXR. The relation between efficacy and antigen density was examined on 10 xenograft models bearing cancer cells with varying GAH reactivity. Immunoliposomal doxorubicin therapeutic activity correlated with the antigen density, with a minimum number being required. Also, ILD revealed strong antitumour activity on cancers with low sensitivity to DXR or LD, suggesting that ILD overcame the DXR resistance of antigen-positive cancer cells. Thus, these results show that GAH endows liposomes with targeting activity, resulting in strong efficacy against gastrointestinal cancers.
Hosokawa
S
S
Pharmaceuticals Research Division, Mitsubishi Pharma Coporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
Tagawa
T
T
Niki
H
H
Hirakawa
Y
Y
Nohga
K
K
Nagaike
K
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D000954:Antigens, Surface / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D003110:Colonic Neoplasms; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011092:Polyethylene Glycols; D012997:Solvents; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D008081:Liposomes; D012997:Solvents; D011092:Polyethylene Glycols; D004317:Doxorubicin