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

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  • Kimotsuki Tomofumi
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
  • Tanaka Kohji
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
  • Sugiura Tomomi
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
  • Koyama Kumiko
    Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd.
  • Nakamura Takahiro
    Drug Safety Research Laboratories, Shin Nippon Biomedical Laboratories, Ltd.
  • Kamimura Yasuhiro
    Drug Safety Research Laboratories, Shin Nippon Biomedical Laboratories, Ltd.
  • Takasaki Wataru
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
  • Manabe Sunao
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.

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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. <br>

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