Thirteen-week Intravenous Toxicity Study of a Novel Humanized Anti-Human Death Receptor 5 Monoclonal Antibody, CS-1008, in Cynomolgus Monkeys

Abstract

CS-1008, a humanized monoclonal antibody that is agonistic to human death receptor 5, was intravenously administered to cynomolgus monkeys twice a week for 13 weeks at 3 different dose levels (5, 15 and 42 mg/kg) in order to evaluate its potential toxicity. A control group received phosphate buffered saline containing 0.01% polysorbate 80. Each of the 4 groups consisted of 3 male and 3 female cynomolgus monkeys. No animal in any group died during the dosing period. No toxic changes in clinical signs, food consumption, body weight, electrocardiography, ophthalmology, urinalysis, hematology, blood chemistry, gross pathology, organ weights or histopathology were noted in any group during the dosing period. In the toxicokinetic analysis, the values for the maximum concentration of CS-1008 in plasma and the area under the curve generally increased with increasing dose. No clear differences in the toxicokinetic parameters or profiles were observed between the sexes. Development of anti-CS-1008 antibodies was not detected in any sample. The no-observed adverse-effect level (NOAEL) of CS-1008 in cynomolgus monkeys under the conditions of this study was concluded to be 42 mg/kg in both sexes, when administered intravenously twice a week for 13 weeks. This study supports the development of CS-1008 as a therapeutic biopharmaceutical.

Novel Immunoliposome Technology for Enhancing the Activity of the Agonistic Antibody against the Tumor Necrosis Factor Receptor Superfamily

“…Some reports have described the hepatotoxicity of the anti-DR5 antibody. ,,, TRA-8 does not induce apoptosis in normal hepatocytes or, even if it does, it is very weak. In addition, the efficacy of TRA-8 for tumor cells is relatively weak.…”

Multimeric Anti-DR5 IgM Agonist Antibody IGM-8444 Is a Potent Inducer of Cancer Cell Apoptosis and Synergizes with Chemotherapy and BCL-2 Inhibitor ABT-199

“…DR5 is a promising cancer therapeutic target more highly expressed on cancer cells than normal human tissues, providing selective tumor killing (2,3). Recombinant TRAIL and anti-DR5 agonistic IgG antibodies have demonstrated efficacy in preclinical mouse tumor models (4)(5)(6)(7)(8)(9) and were safe in cynomolgus monkeys (10,11). Although these agents were generally well tolerated in patients, there were select reports of on-target, off-tumor drug-induced hepatotoxicity (12,13).…”