Experimental treatment of malignant gliomas with human monoclonal antibody-drug conjugates.
This study was designed to determine whether the monoclonal antibody-drug conjugates are more potent than the free drugs in killing human glioma cells in vitro and in vivo. The anticancer drugs doxorubicin (DXR) and 4'-epi-doxorubicin (epi-DXR) were separately conjugated to the human monoclonal antibody (mAb) CLNIgG, which binds strongly to human malignant glioma cells. The cytotoxic activity of the mAb-drug conjugates was assessed by a 3H-thymidine assay in vitro. The efficacy, biodistribution and autography of the immunoconuugates were examined using the subcutaneous glioma model (nude mouse). The epi-DXR-CLNIgG conjugate was found to be 11 times more potent than free epi-DXR in killing glioma cells in vitro, and epi-DXR-CLNIgG clearly achieved the most favorable antitumor effects. A biodistribution study using [14-14C]DXR-CLNIgG at the conjugate indicated that the immunoconjugates delivered DXR to glioma tissues at least five times more than the free DXR alone in nude mice without increasing the concentration in other tissues. An autoradiographic study also showed good accumulation of the antibody-drug conjugate in the subcutaneously transplanted glioma. Thus, the human monoclonal antibody-drug conjugates constitute a potential new approach for the treatment of malignant gliomas.
Takahashi
H
H
Department of Neurosurgery, Nippon Medical School, Tokyo, Japan. hitaka84@nms.ac.jp
Adachi
K
K
Yamaguchi
F
F
Teramoto
A
A
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D015251:Epirubicin / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D013997:Time Factors; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D015251:Epirubicin; D004317:Doxorubicin