Exploration Of The Toxicity Of A Biosimilar Of Pertuzumab And Recombinant Human-derived Antibody Of HER-2 In Cynomolgus Monkeys Fellowing Repeated Administration

Part One A Research of Dose about a Biosimilar of PertuzumabObjective: To evaluate the toxicity of a biosimilar of pertuzumab,in cynomolgus monkeys following repeated intravenous for 4 weeks,ensure the dose of the NOAEL.Methods: According to the body weight,twenty healthy cynomolgus monkeys were randomly divided into 5 groups with 4 animals(half male and half female)in each group.Animals were subcutaneously treated once a week for 4 weeks with a biosimilar of pertuzumab(0、15、150 or 450 mg/kg),Pertuzumab(150 mg/kg)following a recovery period of 4 weeks.The injection volume was 15.0 m L/kg,while the rate of the administration was about 5 m L/min.Toxicological indexex were recorded during the test.Results: The general symptom results showed that there were animals who had diarrhea gradually after the administration in low dose group,middle dose group,high dose group and pertuzumab.The first animal who had diarrhea was one of high dose group and was dead on d40.The dead animal’s ALP was arised on d28,BU was arised on d14 and d40,while TP and ALB were decreased.Compared with d0(before administration)in the same group,WBC decreased significantly in low dose group,high dose group and pertuzumab,while BU was increased in all groups on d14.BU in high dose group and pertuzumab was increased on d28.The above changes were reversible at the end of the recovery period.The analysis of the dead animal showed that the red blood cell and bare nucleus were increased,while the granulocyte was decreased.Pathological examination show that there were tubular dilatation and abnormal in proximal tubule.The other indexes were not affected by the administration of the drug.Conclusion: The main toxic target organs of a biosimilar of pertuzumab are gastrointestinal(diarrhea),kidney(the increased of the BU in serum)and blood system(the decreased of the WBC).The NOAEL of a biosimilar of pertuzumab is 150 mg/kg.The poisoning dose is 450 mg/kg.The toxicities of a biosimilar of pertuzumab are comparable to those of pertuzumab at the same dose.Part Two Toxicity Exploration and Research of a Biosimilar of Pertuzumab,Following 13 Weeks Repeated AdministrationObjective: To evaluate the toxicity of a biosimilar of pertuzumab,in cynomolgus monkeys following repeated intravenous for 13 weeks.Methods: According to the body weight,forty healthy cynomolgus monkeys were randomly divided into 4 groups with 10 animals(half male and half female)in each group.Animals were subcutaneously treated once a week for 13 weeks.The first week was treated with a biosimilar of pertuzumab(0、30、100 and 300 mg/kg),then was treated with a biosimilar of pertuzumab(0、15、50 and 150mg/kg)on week 2-4 then following a recovery period of 4 weeks.The first injection volume was 15.0 m L/kg,while the injection volume of the other weeks was 7.5 m L/kg.Toxicological indexex were recorded during the test.Results: The general symptom results showed that there were animals who had diarrhea gradually after the administration in low dose group,middle dose group and high dose group.Compared with d0(before administration)in the same group,RBC、Hb and Hct were decreased slightly,while RETIC% was increased.BU and Cr were increased while TP and ALB were decreased.The above changes were reversible at the end of the recovery period.The other indexes were not affected by the administration of the drug.Conclusion: The main toxic target organs of a biosimilar of pertuzumab are gastrointestinal and kidney,The drug has some immunity in cynomolgus monkeys,The NOAEL of the biosimilar of pertuzumab is 150 mg/kg(300 mg/kg for the first week).Part Three Toxicity Exploration of recombinant human-derived antibody of HER-2 after repeated administrationObjective: To evaluate the toxicity of recombinant human-derived antibody of HER-2,in cynomolgus monkeys following repeated intravenous for 4 weeks.Methods: According to the body weight,70 healthy cynomolgus monkeys were randomly divided into 7 groups with 10 animals(half male and half female)in each group.Animals were subcutaneously treated once a week for 4 weeks with a recombinant human-derived antibody of HER-2(0、60、200 or 600 mg/kg)for the first week and 0、30、100 or 300 for the 2-4 weeks.Herceptinand a biosimilar of trastuzumab and a biosimilar of pertuzumab were treated with 300mg/kg for the first week and with 150 mg/kg for the 2-4 week.Following a recovery period of 6 weeks.Toxicological indexex were recorded during the test.Results: The toxicity of the combination showed that the main reaction was diarrhea.RBC,HGB,HCT,TP and ALB were decreased,while AST,GGT,TBIL,BU,CREA,CPK and LDH were arised.The nucleated red cell of the high dose group was active.The pathological examination showed that there were pathological changes in stomach,duodenum and liver.Conclusion: The NOAEL of recombinant human-derived antibody of HER-2 is 30 mg/kg(60 mg/kg for the first week),The target organ of the combination are the system of digestive,blood and urinary.Compared with provide alone,the combination doesn’t wrose the toxicity.