Specific targeting of chlorambucil to tumors with the use of monoclonal antibodies.
The concept of attaching cytotoxic drugs, such as the alkylating agent chlorambucil (CBL), to "tumor-specific" antibodies for the treatment of cancer is attractive, inasmuch as the specificity of CBL could be increased and its systemic toxicity reduced. To this end, CBL was activated by N-hydroxysuccinimide to produce an active ester derivative that was covalently coupled to monoclonal antibodies reactive with murine cell surface antigens. Up to 30 molecules of CBL were specifically bound per molecule of antibody, without impairing the alkylating activity of CBL and with minimal loss of antibody activity. The in vitro cytotoxicity of the conjugate was tested by the inhibition in [3H]thymidine incorporation into tumor cells, which demonstrated the conjugate to be specifically cytotoxic toward antibody-reactive cell lines, having more activity than the free drug. In vivo treatment of (C57BL/6 X BALB/c)F1 mice bearing a murine thymoma with CBL-antibody conjugates gave prolonged survival times and greater inhibition of growth of established tumors than was obtained with free antibody or CBL alone. The study is one of the first examples of the greater toxicity of a drug coupled to antibody, inasmuch as most drugs when coupled to antibody lose activity. CBL-monoclonal antibody conjugates may, therefore, provide a means of specifically attacking tumors, which could be therapeutically useful.
Smyth
M J
MJ
Pietersz
G A
GA
Classon
B J
BJ
McKenzie
I F
IF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D002460:Cell Line; D002699:Chlorambucil / Q000008:administration & dosage* / Q000627:therapeutic use; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013936:Thymidine / Q000378:metabolism; D013945:Thymoma / Q000188:drug therapy; D014316:Tritium
D000911:Antibodies, Monoclonal; D014316:Tritium; D002699:Chlorambucil; D013936:Thymidine