Target-mediated drug disposition and prolonged liver accumulation of a novel humanized anti-CD81 monoclonal antibody in cynomolgus monkeys.
CD81 is an essential receptor for hepatitis C virus (HCV). K21 is a novel high affinity anti-CD81 antibody with potent broad spectrum anti-HCV activity in vitro. The pharmacokinetics (PK), pharmacodynamics and liver distribution of K21 were characterized in cynomolgus monkeys after intravenous (i.v.) administration of K21. Characteristic target-mediated drug disposition (TMDD) was shown based on the PK profile of K21 and a semi-mechanistic TMDD model was used to analyze the data. From the TMDD model, the estimated size of the total target pool at baseline (V(c) • R(base)) is 16 nmol/kg and the estimated apparent Michaelis-Menten constant (KM) is 4.01 nM. A simulation using estimated TMDD parameters indicated that the number of free receptors remains below 1% for at least 3 h after an i.v. bolus of 7 mg/kg. Experimentally, the availability of free CD81 on peripheral lymphocytes was measured by immunostaining with anti-CD81 antibody JS81. After K21 administration, a dose- and time-dependent reduction in free CD81 on peripheral lymphocytes was observed. Fewer than 3% of B cells could bind JS81 3 h after a 7 mg/kg dose. High concentrations of K21 were found in liver homogenates, and the liver/serum ratio of K21 increased time-dependently and reached ~160 at 168 h post-administration. The presence of K21 bound to hepatocytes was confirmed by immunohistochemistry. The fast serum clearance of K21 and accumulation in the liver are consistent with TMDD. The TMDD-driven liver accumulation of the anti-CD81 antibody K21 supports the further investigation of K21 as a therapeutic inhibitor of HCV entry.
Non-Clinical Safety; Nutley, NJ USA.
Vladimir
V
Vexler
Li
L
Yu
Chandrasena
C
Pamulapati
Rosario
R
Garrido
Hans Peter
HP
Grimm
Priya
P
Sriraman
Sandhya
S
Bohini
Michael
M
Schraeml
Usha
U
Singh
Michael
M
Brandt
Stefan
S
Ries
Han
H
Ma
Klaus
K
Klumpp
Changhua
C
Ji
D061605:Administration, Intravenous; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics*; D000915:Antibody Affinity / Q000276:immunology; D019540:Area Under Curve; D016466:CHO Cells; D002478:Cells, Cultured; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D016503:Drug Delivery Systems / Q000379:methods; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D018613:Microscopy, Confocal; D008954:Models, Biological; D060225:Tetraspanin 28 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
D061067:Antibodies, Monoclonal, Humanized; D060225:Tetraspanin 28
CD81; PD; PK; TMDD; cynomolgus monkey; liver distribution; mAb