In vitro and in vivo cytotoxic activity of anti-human leukemia monoclonal antibodies SN5c and SN6 daunorubicin conjugates.
Murine monoclonal antibodies SN5c specific for the common acute lymphoblastic leukemia antigen (CALLA) and SN6 specific for a novel GP160 tumor associated antigen expressed on non-T ALL and myelomonocytic leukemia cells were conjugated to daunorubicin via an intermediate dextran carrier. The resulting monoclonal antibody-daunorubicin conjugates retained the immunoreactivity of the unlabeled antibody to antigen positive leukemia target cells. In addition, these conjugates demonstrated selective cytotoxic activity when tested against a panel of human leukemia cell lines and/or human leukemia patient samples of peripheral blood or bone marrow origin. The SN5c and SN6-daunorubicin immunoconjugates were superior to a non-specific isotype matched MOPC-daunorubicin conjugate in in vitro cytotoxicity assays. Free daunorubicin, however, was more cytotoxic than either immunoconjugate but lacked selectivity. SN5c-daunorubicin and SN6-daunorubicin combined were as effective as free daunorubicin when used for in vivo therapy and led to complete ablation of established NALM-6 tumors in an athymic nude mouse model. The SN5c-daunorubicin conjugate was also shown to be significantly less toxic than free daunorubicin in non-tumor bearing Balb/c mice. These studies indicate that mAb-daunorubicin conjugates can be constructed which retain specific binding and exhibit selective cytotoxicity against human leukemia cells and suggest that they may have therapeutic applications.
Biddle
W C
WC
Department of Clinical Immunology, Roswell Park Memorial Institute, Buffalo, NY 14263.
Haruta
Y
Y
Seon
B K
BK
Henderson
E S
ES
Sarcione
E J
EJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use / Q000633:toxicity; D000943:Antigens, Differentiation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy*; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D007938:Leukemia; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015260:Neprilysin
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D000922:Immunotoxins; D015260:Neprilysin; D003630:Daunorubicin