Rituximab LYQ-1124:Pharmacokinetic And Pharmacodynamics Study In Cynomolgus Monkeys

LYQ-1124 is chimeric monoclonal antibody rituximab which can combine specifically with B lymphocytes CD20 antigen to cause B cells dissolved.It is developed for the treatment of relapsed or refractory central follicular lymphoma,previously untreated CD20-positive stage III-IV follicular non-Hodgkin's lymphoma,and CD20positive diffuse large B cell non-Hodgkin's lymphoma.The purpose of this study is to evaluate the pharmacokinetic characteristics,immunogenicity and the changes of pharmacodynamic markers and compare LYQ-1124 with the original drug MabThera in various aspects at the same dose following single or repeat dosing in cynomolgus monkeys.Thirty cynomolgus monkeys,divided into 5 groups randomly?3/sex/group?were single dosed with LYQ-1124?10,30 and 100 mg/kg?or MabThera?30 mg/kg?or once weekly,total 4 does with LYQ-1124?30 mg/kg?.Serum samples were collected for the measurements of plasma concentration,ADA and PD biomarkers.Pharmacokinetic?PK?The drug concentration in the serum was determined by enzyme linked immunosorbent assay?ELISA?and the PK parameters were calculated by non-compartment model.The mean T_maxax after single dose of LYQ-1124 or MabThera were 0.0290,0.0099,0.0770 and 0.0162d;Mean C_max and AUC0-83d were increased with the increase of the dosage;the mean clearance rate?CL?were 12.1,7.9,10.0 and9.7 mL/day/kg;mean T_1/2 were 2.17,4.28,3.74 and 3.66d.The pharmacokinetic parameters were similar in the LYQ-1124 and rituximab group under the same dose.The mean C_SS is about 288?g/ml after 4 times repeating dose of LYQ-1124.And concentrations before the 2^nd,3^rd,and 4^th dose were approximately 153,175 and 154?g/ml.No obvious drug accumulation was found after repeating dose.No obvious gender differences were found in the PK parameters.Anti-drug antibodyThe ADA in serum was detected by bridge ELISA.ADA was detected on Day 21,42,42,21 respectively for the single dose group of LYQ-1124 or MabThera.Till Day 83,ADA was detected for total 95.8%?23/24?animals.The titer range of ADA in each group was 1:1800-1:324000,1:1800-1:108000,1:300-1:36000 and 1:900-1:108000 and the titer were decreased with the increase of dose levels.ADA detection rate and the titer are similar in the LYQ-1124 and MabThera group under the same dosage.The results showed that no effects on drug concentration were caused by ADA and the immunogenicity of both LYQ-1124 and MabThera were similar.ADA was detected on Day 42 to 83 in total 50%?3/6?animals in the repeating dose group.The titer range was 1:1800-1:108000.ADA in 1 animal had affected the metabolism of drugs.Pharmacodynamics?PD?biomarkerSignificantly decreasing of lymphocytes CD3-CD20+of peripheral blood was found in each group after single dose of LYQ-1124 or MabThera.It decreased to 1.2%,0.3%?0.3%and 2.4%at 24h post dose and still kept at 1.1%,0.2%,0.2%and 0.3%on Day 8.After that,CD3-CD20+%began to recovery gradually.The recovery is more slowly in the higher dose.CD3-CD20+%had not recovered to the level of pre-dose phase till Day 83.Rapid and sustained reduction in peripheral blood CD3-CD20+%was found in the repeating dose group.CD3-CD20+%was maintained between 0.0-1.1%continuously and recovered slowly after stop dosing.It recovered to 50.1%till Day 83.No obvious gender differences were found in CD3-CD20+%.