Page 189 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

Towards 89Zr-immuno-PET to measure target engagement of antibodies
DISCUSSION
89Zr-immuno-PET is a promising, non-invasive clinical tool to measure antibody target engagement in-vivo. As a first step towards quantification of target engagement, non-specific uptake for tissues without target expression was assessed for four 89Zr-labeled mAbs. This study showed that non-specific, reversible uptake (VT) was similar to the predicted value for a non-binding mAb. Non-specific, irreversible uptake (Ki) corresponded with the predicted value for the fractional catabolic rate of IgG. Patlak linearization is applied to data obtained from a single subject. The range of values observed for the baseline transfer constants reflects inter-patient variability. This method allows, for a single subject, to assess whether target-mediated binding does occur in a certain normal tissue for the antibody under investigation. Similar as for PKPD type analysis, Patlak linearization can be applied with sparse temporal sampling, but does not require assumptions that underlying parameters are the same among patients. Moreover, it uses the individually measured input functions, i.e. bioavailability of the tracer in blood over time and it can therefore account for inter-individual variability of the tracer bioavailability in the central compartment (i.e. blood). For these reasons this method was applied in our present study. An increase in Ki indicates target engagement, as was observed for e.g. 89Zr-antiPSMA in the kidney. In this study, baseline values for Ki and VT were tissue dependent. Especially for the liver, relatively high non-specific, irreversible uptake was observed compared to other tissues, indicating that this organ is strongly involved in mAb catabolism. Therefore, detection of target engagement with a single uptake value is expected to be more difficult in the liver.
Study design can have a significant impact of the ability to detect target engagement. For example, for 89Zr-antiCD20, no increase of irreversible uptake 9 (Ki) was observed in the spleen, although expression of CD20 in the spleen is
known to be high (20). A plausible explanation for this observation is saturation of
the CD20 receptors due to high dose of unlabeled antiCD20 (1000mg), which was administered before the radiolabeled antibody. So, antibody dose is a parameter to
be taken into account in assessment of target engagement. Another important consideration for design of 89Zr-immuno-PET studies, is that scans obtained at
multiple late time points are required for the Patlak linearization to determine
reversible and irreversible uptake. At least 3 late time points are required to assess
whether the data can be fitted to a straight line.
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