Physiologically based pharmacokinetic model for T84.66: a monoclonal anti-CEA antibody.
Antibodies directed against tumor associated antigens are being increasingly used for detection and treatment of cancers; however, there is an incomplete understanding of the physiological determinants of antibody pharmacokinetics and tumor distribution. The purpose of this study is to (a) compare the plasma pharmacokinetics of T84.66, a monoclonal anti-CEA antibody directed against tumor associated carcinoembryonic antigen (CEA), in control and CEA expressing LS174T xenograft bearing mice, and (b) to develop a physiologically based pharmacokinetic (PBPK) model capable of integrating the influence of CEA and the IgG salvage receptor, FcRn, on T84.66 disposition. T84.66 pharmacokinetics were studied following i.v. administration (1, 10, 25 mg/kg) in control and xenograft bearing mice. In control mice, no significant differences in clearance were observed across the dose range studied. In mice bearing xenograft tumors, clearance was increased by four- to sevenfold, suggesting the presence of a "target mediated" elimination pathway. T84.66 plasma disposition was characterized with a PBPK model, and the model was applied to successfully predict antibody concentrations in tumor tissue. The PBPK model will be used to assist in the development of antibody-based targeting strategies for CEA-positive tumors.
Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14260, USA.
Shweta R
SR
Urva
Victor C
VC
Yang
Joseph P
JP
Balthasar
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015233:Models, Statistical; D009369:Neoplasms / Q000378:metabolism; D011961:Receptors, Fc / Q000378:metabolism; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; C100688:Fc receptor, neonatal