Antigen-specific activity of carcinoma-reactive BR64-doxorubicin conjugates evaluated in vitro and in human tumor xenograft models.
The anticarcinoma antibody BR64 was conjugated to a doxorubicin derivative, doxorubicin 13-[3-(2-pyridyldithio)propionyl]hydrazone, and the resulting conjugates (BR64-DOX) were evaluated for activity and immunological specificity in vitro and in human tumor xenograft models. The BR64-DOX immunoconjugates retained immunoreactivity and cytotoxicity and demonstrated antigen-specific cytotoxicity in vitro. The potency of BR64-DOX immunoconjugates in vitro was related to the drug:monoclonal antibody mole ratio of the conjugates. The antitumor activity of BR64-DOX conjugates was consistently superior to the maximal activity obtained with the parent drug, doxorubicin (DOX), in established human lung and human breast carcinoma xenograft models. The superior antitumor activity of BR64-DOX conjugates was reflected both in tumor growth inhibition and in regressions and cures of established tumors following the administration of tolerated doses of BR64-DOX. The antitumor activity of BR64-DOX conjugates was not the result of synergism between monoclonal antibody BR64 and DOX, because mixtures consisting of monoclonal antibody and optimized DOX were not more active than an equivalent dose of DOX administered alone. The antitumor activity of BR64-DOX conjugates was antigen specific; equivalent doses of nonbinding isotype-matched conjugates were not active against established tumor xenografts.
Trail
P A
PA
Department of Experimental Therapeutics, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492.
Willner
D
D
Lasch
S J
SJ
Henderson
A J
AJ
Greenfield
R S
RS
King
D
D
Zoeckler
M E
ME
Braslawsky
G R
GR
D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D004317:Doxorubicin / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D000939:Epitopes / Q000032:analysis / Q000276:immunology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D000922:Immunotoxins / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D000939:Epitopes; D007074:Immunoglobulin G; D000922:Immunotoxins; D004317:Doxorubicin