Page 179 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

Towards 89Zr-immuno-PET to measure target engagement of antibodies
INTRODUCTION
In-vivo assessment of target engagement is of interest to understand efficacy (tumor selectivity) and toxicity (due to target expression in normal tissues) of treatment with monoclonal antibodies (mAbs) or mAb conjugates. Currently, only plasma concentrations of mAbs can be easily measured in-vivo by obtaining blood samples. Direct measurement in tissues is difficult, as this requires invasive tissue sampling, limiting clinical application.
89Zr-immuno-PET is a non-invasive, whole body technique with the potential to measure target engagement of therapeutic antibodies (or mAb conjugates) in-vivo (1). Future applications of this clinical tool are selection of mAbs during drug development and selection of patients who are likely to benefit from treatment (2).
Currently, it is common practice to report a single uptake value, expressed
as standardized uptake value (SUV) or percentage injected activity per mL (%IA/
mL) for 89Zr-immuno-PET. However, the measured uptake in tissue is the sum of
specific uptake (target engagement by the therapeutic antibody) and non-specific
uptake (i.e. activity in the blood vessels or in the interstitial space that does not
interact with the target and therefore has no pharmacologic effects). The ratio
between specific uptake and non-specific uptake is expected to be time dependent.
Measured uptake at early time points mainly consists of the blood volume fraction,
while specific uptake increases over time. If specific uptake dominates, a single
uptake value is an appropriate estimate to assess target engagement (3). This measurement is then expected to correlate with target expression in biopsies (determined by immunohistochemistry) and treatment outcome. However, also
biopsy sampling has several limitations, e.g. sampling error and heterogeneity in
target expression. Although biopsies may not provide a true gold standard for 9 target engagement, it is the commonly available comparator. So far, clinical 89Zr- immuno-PET studies have reported equivocal results; sometimes suggesting a
correlation and sometimes not (4-7). These results indicate that a single uptake
value could be insufficient due to the contribution of non-specific uptake.
Therefore, knowledge of non-specific uptake is required to optimize study design.
The aim of this study was to assess non-specific uptake for tissues without target expression, as a first step towards quantification of target engagement using 89Zr-immuno-PET.
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