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

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]