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Abstract
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.
2009 Wiley-Liss, Inc. and the American Pharmacists Association