Nonclinical Pharmacokinetics Of Recombinant Human Complete Monoclonal Antibody Against EGFR

Objective:To study the pharmacokinetics of recombinant human complete monoclonal antibody against EGFR in cynomolgus monkeys and its tissue distribution and excretion characteristics in mice.Methods:The pharmacokinetics of recombinant human complete monoclonal antibody against EGFR in cynomolgus monkeys was studied by ELISA,and PK analysis was carried out.The anti EGFR monoclonal antibody was labeled by radioisotope ¹²⁵I,The tissue distribution,excretion of feces and urine,excretion of bile and binding with plasma protein of anti EGFR monoclonal antibody were studied by TCA precipitation method and SHPLC.Results:1.After a single intravenous infusion of different doses（1.5,7.5,37.5mg/kg）of recombinant human complete monoclonal antibody against EGFR,with the increase of the dosage,the serum drug exposure level increased nonlinearly,the half-life of the terminal phase extended gradually,the system clearance rate decreased gradually,showing obvious nonlinear pharmacokinetic characteristics.2.After intravenous infusion of 7.5 mg/kg anti EGFR monoclonal antibody once a week and four times in a row,compared with the first administration,the blood concentration and main pharmacokinetic parameters of most of the animals at the same time point were statistically different.All the animals showed different levels of drug accumulation after the last Administration,and the blood concentration basically reached a steady state after multiple administration.3.Compared with the same dose of cetuximab（7.5 mg/kg）,the clearance rate of anti EGFR monoclonal antibody was significantly lower than that of cetuximab,the half-life of terminal phase was significantly longer than that of cetuximab,and the drug exposure level was significantly higher than that of cetuximab.4.After ¹²⁵I-anti EGFR monoclonal antibody was injected intravenously,the drug was widely distributed in most tissues and organs of the whole body,and the tissue with abundant blood flow had a higher radioactive distribution,while the tissue with insufficient blood flow had a lower radioactive distribution.5.the concentration of ¹²⁵I-anti EGFR monoclonal antibody in brain and bone marrow was low,suggesting that the drug was not easy to penetrate the blood-brain barrier.6.¹²⁵I-anti EGFR monoclonal antibody has a high concentration of radioactivity in the tumor site,which is time-dependent and reaches the peak at 72h.The data of in vivo imaging also further proves that the drug targets the tumor site.7.The rate of radioactive excretion was slow after ¹²⁵I-anti EGFR monoclonal antibody was injected into the vein of tumor bearing nude mice,which was mainly excreted by urine,part by feces and a little by bile.8.After administration,the blood of tumor bearing nude mice was mainly drug prototype,and no binding phenomenon of ¹²⁵I-anti EGFR monoclonal antibody with plasma protein was found.Conclusions:The level of drug exposure of anti EGFR monoclonal antibody in cynomolgus monkeys was significantly higher than that of cetuximab,and showed obvious nonlinear pharmacokinetic characteristics.¹²⁵I-anti EGFR monoclonal antibody has the ability of tumor targeting in nude mice,mainly through renal metabolism.