Evaluation of human monoclonal antibody toxicity, toxicokinetics and immunogenicity in cynomolgus monkeys after 4-week repeat IV dose with 4-week recovery

OBJECTIVE The aim of this study was to characterize the toxicity of the antibody and in particular,the exposure-response relationship of the immune-mediated toxicity between these two dose regimens.METHODS 36 cynomolgus monkeys（6 monkeys /sex /group,3 groups） were given intravenous doses of the antibody at either 15 mg /kg QW or 30 mg·kg-1 Q2W for 4 weeks followed by 4 weeks recovery.The following were assessed for all animals: clinical observations（cage side observations,detailed clinical observations,physical examinations /clinical assessments and injection site observations）,body weight,food consumption,ophthalmology,ECG,blood pressure haematology,coagulation,blood chemistry,urine analysis,levels of concentration of the antibody,toxicokinetics,immunogenicity（anti-drug antibody,ADA） in serum and gross and microscopic pathology.RESULTS AND CONCLUSION The antibody caused histopathological changes in the liver and clinical pathological changes were seen including decreases in albumin /globulin ratios and in white blood cell counts.However,the changes in histopathology and clinical pathological parameters were all recovered at the end of the recovery period.The monkeys given multiple intravenous doses of 15 mg·kg-1 QW or 30 mg·kg-1 Q2W of the antibody showed comparable serum exposures,assessed by AUC and the serum CL was similar between these two dose regimens.About 16.7% of monkeys developed ADA while receiving 15 mg·kg-1 QW antibody,whereas 25% of monkeys developed ADA after receiving 30 mg·kg-1 Q2W.All ADA positive animals were female and the presence of ADA in these animals was associated with reduced TK exposures.Given the non adverse nature of the findings,both dose regimens,15 mg·kg-1 QW and 30 mg·kg-1 Q2W,were considered no-observed-adverse-effect levels.