Twenty-six-week repeated dose toxicity and immunotoxicity study of an anti-PD-1 monoclonal antibody in cynomolgus monkeys
Objective To evaluate the toxicity of Anti-PD-1 monoclonal antibody injection and study its immunotoxicity,and to provide target organs for toxic reactions and observe the reversibility of damage after four weeks of recovery,so as to provide reference for clinical trials.Methods Cynomolgus monkeys were given low,medium and high doses(6,40,100 mg/kg)of anti-PD-1 monoclonal antibody injection(F520)by intravenous injection,once a week for 26 consecutive weeks,control groups were given the same volume of vehicle.During the experiment,the general state of the animals,moribund/mortality situation,the body weight,food intake,body temperature,electrocardiogram,ophthalmology,toxicokinetics study,immunogenicity study,T cell-dependent antibody response,body mass,cytokine detection,hematology and coagulation indexes,serum biochemical indexes,immune function,urinalysis,fecal occult blood,bone marrow smear,CD69 activation level,organ weight and coefficient,gross anatomy and histopathology and kidney Immunohistochemistry and other items were checked.Results There was no moribund/mortality situation,and no obvious abnormality was found in clinical observation,body weight,food intake,body temperature,electrocardiogram(lead Ⅱ),ophthalmology,hematology and coagulation indexes,serum biochemical indexes,and stool and urine tests.Flow cytometric phenotype analysis and in vivo antibody and complement levels showed no obvious abnormality.IL-6 of individual animals in high-dose group was slightly elevated in cytokine detection.Histopathological examination revealed multi-organ arteritis/periarterial lymphocyte infiltration in the middle and high dose groups.Conclusion Cynomolgus monkeys were given a anti-PD-1 monoclonal antibody injection once a week for 26 consecutive weeks,at doses of 6,40,and 100 mg/kg,respectively.The highest non-severely toxic dose(Highest Non-Severely Toxic Dose,HNSTD)was 100 mg/kg.
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