Human monoclonal antibody-drug conjugates in the experimental treatment of malignant gliomas--studies in vitro and in vivo.
The chemotherapeutic agents doxorubicin (DXR) and 4'-epi-doxorubicin were separately conjugated to the human monoclonal antibody CLNIgG, which binds strongly to human malignant glioma cells. The antibody-drug conjugates were more potent than the free drugs in killing human glioma cells in vitro and in vivo (subcutaneous glioma model). A biodistribution study using [14-14C]DXR-CLNIgG conjugate indicated that immunoconjugates delivered at least five times more DXR to glioma tissues than free DXR alone in nude mice without increasing the concentration in other tissues. In a nude rat intracerebral glioma model, intracarotid hyperosmolar perfusion to achieve blood-brain barrier (BBB) opening caused a 640% increase in the DXR-CLNIgG concentration in intracerebral tumor tissue. Human monoclonal antibody-drug conjugates in combination with BBB opening is a potential new approach to the treatment of malignant gliomas.
Zhu
J
J
Department of Neurosurgery, Nippon Medical School, Tokyo.
Takahashi
H
H
Nakazawa
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000473:pathology* / Q000628:therapy; D004317:Doxorubicin / Q000494:pharmacology* / Q000627:therapeutic use; D015251:Epirubicin / Q000494:pharmacology / Q000627:therapeutic use; D005910:Glioma / Q000473:pathology* / Q000628:therapy; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured / Q000473:pathology
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D015251:Epirubicin; D004317:Doxorubicin