Page 184 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer
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Chapter 9
The quality of the linear fit was assessed if at least 3 late time points were available. An r-value>0.9 was considered acceptable. Linear fits with an r-value <0.9 were excluded from the analysis.
The reversible and irreversible contributions to the uptake of 89Zr-mAb (ACf) at each time point were calculated as
,
with superscript r for the reversible and i for the irreversible component. In addition, the percentage difference between fitted (ACf = ACr + ACi) and measured tissue activity concentrations per time point was calculated as (ACf-ACt)/ACt x 100 (%).
Predicted Values for Transfer Constants
The transfer constants obtained were interpreted in terms of physiological components of antibody biodistribution. A literature search was performed to obtain predicted values for these physiological components for a non-binding intact IgG1 mAb.
To predict the value for the reversible component for a non-binding mAb, we used the proportionality constant between the tissue and plasma concentration, referred to as the antibody biodistribution coefficient (ABC). ABC for various tissues were obtained by a physiologically-based pharmacokinetic (PBPK) model of mAbs and validated with experimental data (9). The reported ABC for brain was 0.004 (9), indicating that the plasma volume fraction of 0.02 (22) was not included. Therefore, we defined the predicted value for VT as the ABC plus the plasma volume fraction (within a 2-fold error margin, as reported for all ABC). The volume fraction was calculated as the plasma volume of the tissue (in mL) divided by the total volume of the tissue (in mL). Plasma and total tissue volumes were obtained from previously published physiological model parameters for human (22). For example, for the kidney, the reported ABC was 0.137 and the plasma volume fraction 0.055 (22), leading to a predicted VT of 0.19. The predicted values for VT for liver and spleen were 0.21 and 0.25 (9,22). The ABC for lung requires special consideration, since lung has a density of ~0.3g/mL. Volumes of distribution are in mL×cm-3, and therefore the ABC for lung was divided by three in order to compare with VT values derived from 89Zr-immuno-PET. For lung, the predicted value for VT was 0.10 (9,22).
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