Ricin A-chain conjugated with monoclonal anti-L1210 antibody. In vitro and in vivo antitumor activity.
In studies of antitumor antibody-cytotoxic agent conjugates as potential antitumor agents with improved tumor specificity, the toxic subunit A-chain of ricin was conjugated with a monoclonal antibody to a tumor-associated antigen expressed weakly on murine leukemia L1210 cells and strongly on L1210/GZL cells, a guanazole-resistant subline of L1210, employing N-succinimidyl 3-(2-pyridyldithio)propionate as cross-linking agent. The conjugate (anti-L1210 conjugate) exhibited a potent concentration-dependent cytotoxicity against cultured L1210/GZL cells, and inhibited cell growth at concentrations over 0.8 micrograms/ml. The conjugate killed all L1210/GZL cells at a concentration of 100 micrograms/ml. Neither nonimmune conjugate similarly prepared from mouse nonimmune IgG nor unconjugated anti-L1210 IgG alone showed cytotoxicity against L1210/GZL cells. When (BALB/c X DBA/2)F1 mice inoculated with 1 X 10(5) L1210/GZL cells were treated with IP injections of 27 micrograms anti-L1210 conjugate 1 h and 5 days after tumor cell inoculation, a life-prolonging effect was observed. [Lifespan in treated animals as percentage of that in controls (T/C) = 146%]. However, when the dose per injection was increased to 50 micrograms per mouse, survival was the same as in the control group. Postmortem examination of mice that had been treated with 50 micrograms anti-L1210 conjugate revealed lesions with necrosis and hemorrhage in the liver parenchyma and the intestinal epithelium, respectively. A similar toxic effect on the host mice was also observed with nonimmune conjugate.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000502:physiology*; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000502:physiology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000276:immunology; D005260:Female; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000502:physiology; D007167:Immunotherapy; D007939:Leukemia L1210 / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D008223:Lymphoma / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D012276:Ricin / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D012276:Ricin