Ricin A-chain conjugated with monoclonal anti-L1210 antibody |
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Authors: | Kazuo Kishida Yasuhiko Masuho Masahiko Saito Takeshi Hara and Hiroshi Fuji |
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Institution: | (1) Department of Medicinal Chemistry and Biochemistry, Teijin Institute for Biomedical Research, Hino, 191 Tokyo, Japan;(2) Department of Molecular Immunology, Roswell Park Memorial Institute, 14263 Buffaro, NY, USA |
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Abstract: | Summary 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 g/ml. The conjugate killed all L1210/GZL cells at a concentration of 100 g/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×DBA/2)F1 mice inoculated with 1 × 105 L1210/GZL cells were treated with IP injections of 27 g 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 g per mouse, survival was the same as in the control group. Postmortem examination of mice that had been treated with 50 g 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. |
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