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Research Articles: Therapeutics

A two-tiered physiologically based model for dually labeled single-chain Fv-Fc antibody fragments

¹ Biocybernetics Laboratory, Departments of Computer Science and Medicine and Biomedical Engineering Interdepartmental Program, University of California, Los Angeles; ² Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles; and ³ Division of Molecular Biology, Beckman Research Institute of the City of Hope, Duarte, California

Requests for reprints: Gregory Z. Ferl, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at the University of California at Los Angeles, B2-085E CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095-6948. Phone: 310-267-2495; Fax: 310-825-4517. E-mail: gferl{at}mednet.ucla.edu

Monoclonal antibodies (mAb) are being used at an increasing rate in the treatment of cancer, with current efforts focused on developing engineered antibodies that exhibit optimal biodistribution profiles for imaging and/or radioimmunotherapy. We recently developed the single-chain Fv-Fc (scFv-Fc) mAb, which consists of a single-chain antibody Fv fragment (light-chain and heavy-chain variable domains) coupled to the IgG1 Fc region. Point mutations that attenuate binding affinity to FcRn were introduced into the Fc region of the wild-type scFv-Fc mAb, resulting in several new antibodies, each with a different half-life. Here, we describe the construction of a two-tiered physiologically based pharmacokinetic model capable of simulating the apparent biodistribution of both ¹¹¹In- and ¹²⁵I-labeled scFv-Fc mAbs, where ¹¹¹In-labeled metabolites from degraded ¹¹¹In-labeled mAbs tend to become trapped within the lysosomal compartment, whereas free ¹²⁵I from degraded ¹²⁵I-labeled mAbs is quickly eliminated via the urinary pathway. The different concentration-time profiles of ¹¹¹In- and ¹²⁵I-labeled mAbs permits estimation of the degradation capacity of each organ and elucidates the dependence of cumulative degradation in liver, muscle, and skin on FcRn affinity and tumor mass. Liver is estimated to account for 50% of all degraded mAb when tumor is small (0.1 g) and drops to about 35% when tumor mass is larger (0.3 g). mAb degradation in residual carcass (primarily skin and muscle) decreases from 45% to 16% as FcRn affinity of the three mAb variants under consideration increases. In addition, elimination of a small amount of mAb in the kidneys is shown to be required for a successful fit of model to data. [Mol Cancer Ther 2006;5(6):1550–8]

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⁴ V. Kenanova et al., unpublished data.

⁵ GraphPad Prism 4.03. Windows ed: GraphPad Software, San Diego, CA (http://www.graphpad.com).

⁶ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 2/ 7/06; revised 3/29/06; accepted 4/21/06.