Page 171 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

89Zr-immuno-PET in a phase I trial
We observed tumor uptake in all patients receiving ≥ 450 mg, with an extremely high tumor blood volume fraction estimated for the 675 mg cohort. Although this might suggest target-mediated specific tumor uptake, another study design would have been more informative on this point (21). This requires measurement of the same tumor lesion after administration of different antibody doses to exclude differences in tumor characteristics, for example blood volume fraction. Learning from the present study, we recently demonstrated target-mediated specific tumor uptake in a PET imaging study with an anti-HER3 mAb in which the 89Zr-labeled antibody was administered twice (with a variable dose of unlabeled antibody) to a single patient (21). Although biopsies taken after the immuno-PET could have provided additional confirmation with immunohistochemistry, this was not included in the study design due to the fragile patient population.
No focal tumor uptake was visualized in the lowest dose cohorts (1-200 mg). This observation cannot be explained by the level of CD44 expression or the percentage of CD44-positive tumor cells (Table 1). A probable explanation why tumor visualization is hampered for the lowest dose cohorts, is that dose-dependent uptake in normal tissues leads to lower visual tumor contrast, assuming similar binding constants and accessibilities of the target antigen in both normal tissues and tumor. However, in the higher dose cohorts, differences between binding constant became apparent where the dose-dependent tracer uptake in normal tissues does not significantly contribute to the imaging signal anymore (Figure 1), target antigen mediated tracer uptake will result in sufficient visual contrast to allow identification and quantification of tumor targeting.
In this study, PET imaging with the novel anti-CD44 monoclonal antibody 8 RG7356 confirmed tumor uptake for patients receiving ≥ 450 mg. However, dose
dependent uptake of RG7356 in normal tissues indicates target antigen expression,
limiting the use of RG7356 for targeting toxic payloads to the tumor like in antibody-drug conjugate (ADC) approaches.
This exploratory imaging study demonstrates how immuno-PET with a 89Zr-labeled mAb can be used as a general method during phase I dose escalation studies to evaluate the therapeutic potential of an antibody. Evaluation of dose- dependent and dose-independent normal tissue uptake with immuno-PET reflects specific and non-specific uptake. Antibody quantification obtained by molecular imaging provides an additional, non-invasive method to study in vivo mAb biodistribution, besides traditional PK obtained by blood sampling. Especially for a candidate mAb with a potential future as ADC, the resulting information
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