Toxicity of engineered chimeric human-murine anti-EGFR monoclonal antibody AV02 for cynomolgus monkey following repeated intravenous administration

HUANG Yuan-keng; YANG Wei; WANG Xiao-fei; ZHANG Hong; GUO Jian-min; CHEN Zhi-sen

Abstract：Objective:To evaluate the non-clinical safety of engineered chimeric human-murine anti-EGFR monoclonal antibody AV02 for cynomolgus monkeys following repeated intravenous administration,and provide evidences for determining clinical human dosage and monitoring of clinical adverse drug reactions.Methods:Cynomolgus monkeys were randomly divided into four groups including vehicle control,low-,middle-,and high dose of AV02(12/7.5,38/24 and 120/75 mg-kg-1).Each group contained eight monkeys with female and male in half.All animals were intravenously given vehicle or AV02 once a week for 26 weeks followed by 12-week recovery,and the toxicological parameters were determined.Results:Following repeated intravenous administration of test,skin reactions were observed in all dose groups treated with AV02,consisting of exanthema,dry,rough,erythema,desquamation,fissures,hair loss,and corresponding of skin lesions were also finding in histopathology.Serum biochemical analysis showed ALT,γ-GT and GLDH increase and ALB,A/G decrease of the mid-and high-dose groups at weeks 13 and 26,and were reversible within the recovery period.Both absolute and relative mean kidney weights in the mid-and high-dose groups were increased as compared to vehicle control group.One monkey in the low-dose group was considered to have a positive anti-AV02 antibody response.There was no obvious abnormalities in other parameters such as food consumption,body weight,body temperature,body temperature,hematology analysis,immunoglobulin,electrocardiogram,blood pressure,urinalysis,Ophthalmologic examination and bone marrow cell counts,and so on.Conclusion:The main toxicity for AV02 in cynomolgus monkey of the study are pharmacologically-related reactions of skin lesion,a reversible toxicity on liver function,compensatory enlarged kidneys and the low incidence of immunogenic response.Then these indicators should be monitored after the test drugs were given in human clinical trials.These data will facilitate domestic engineered chimeric humanmurine anti-EGFR monoclonal antibody to enter into clinical trial.