Page 190 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer
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                                Chapter 9
In some cases (9/80), the data could not be described by a linear fit. Especially for the lung (4/9), this could be explained by an unfavorable signal to noise ratio (low signal and relative low tissue density). The observed overestimation of fitted uptake data at 24h p.i. accompanied with an underestimation of the uptake at 48-120h p.i. for 89Zr-antiPSMA in the kidney only may indicate that the reversible uptake processes were not yet in the equilibrium state at 24h p.i.. From a methodological perspective, collection of more data points would be preferred. This method could be further validated in future preclinical 89Zr-immuno-PET studies, where scans at more time points can be acquired, including invasive tissue sampling to assess target expression by immunohistochemistry.
Usually, 89Zr-immuno-PET scans are analyzed at a single time point, representing the sum of all physiological components of antibody distribution, being either target specific or non-specific. This study showed how the various physiological components of antibody distribution contribute to the measured SUV (Figure 2 and 3). For the kidney as an example, a SUV of around 2.5 was measured for 89Zr-antiPSMA at 1 to 7days p.i.. Non-specific uptake was estimated to account for a SUV of 1.6 (66%) at 1day p.i.. The contribution of non-specific uptake decreased to a SUV of 0.6 (22%) at 7days p.i..
Detection of target engagement in normal tissues is of interest to assess which mAb has potential for further development into an antibody-drug conjugate (ADC). For an ADC, absence of target engagement in normal tissues is considered important to limit potential toxicity.
To understand and predict efficacy of mAb-based treatments, measurement of target engagement in tumors is essential. However, the method described in this paper cannot be directly applied to tumors, as these are expected to be more complex than normal tissues. Non-specific, reversible uptake in tumors (blood volume fraction and non-target mediated antibody distribution to tumor tissue (“tight or leaky tissue”)) may be more variable between tumors and between patients. In addition, non-specific, irreversible uptake may be increased by the rate of protein catabolism in the tumor and uptake in tumor immune filtrates (e.g. macrophages). In future work, we aim to explore which method can be applied to measure target engagement for tumors. Especially target-negative tumors are of interest to study factors that influence non-specific uptake.
In the present study, 89Zr-immuno-PET was used as a non-invasive clinical tool to assess physiological components of antibody distribution in-vivo and target engagement of therapeutic antibodies was observed. For future studies to assess
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