Page 206 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

Chapter 10
evaluation of transfer constants was used to estimate the reversible (Vt) and irreversible (Ki) contributions to the total measured uptake for the kidney, liver, lung and spleen. At least 3 scans at equilibrium state (≥ 1 day p.i.) are required to assess the quality of the fit. Baseline values were calculated per tissue combining all mAbs without target expression. The transfer constants obtained were interpreted in terms of the 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.
We found that non-specific, reversible uptake was similar to the predicted value for a non-binding mAb (10). Non-specific, irreversible uptake corresponded with the predicted value for the fractional catabolic rate of IgG. In case of target engagement, we expect to observe an increased Ki compared to the baseline value. Expression of PSMA was reported for the kidney and therefore target engagement of 89Zr-antiPSMA is expected in this tissue. For 89Zr-antiPSMA, a four-fold higher Ki was observed for the kidney, indicating target engagement.
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. For example, in the kidney a SUV of ~2.5 was measured for 89Zr-antiPSMA at 1 to 7 days p.i.. Non-specific uptake accounted for a SUV of ~1.6 (66%) at 1 day p.i. and decreased to ~0.6 (22%) at 7 days p.i.. This observation indicates how the contribution of non-specific uptake decreases over time.
“It is sometimes a good idea to develop a new measurement instrument”
This study shows that non-specific uptake of mAbs for tissues without target expression can be quantified using 89Zr-immuno-PET at multiple time points. These results form a crucial base for measurement of target-engagement by therapeutic antibodies in-vivo with 89Zr-immuno-PET. For future studies, a pilot phase including at least 3 scans ≥ 1 day p.i., is required recommended to assess non-specific uptake as a function of time, to optimize study design for detection of target engagement.
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