Page 205 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

In Chapter 8, we investigated application of 89Zr-immuno-PET as a clinical tool to assess antigen-mediated uptake in normal tissues in a phase I dose escalation study, using the anti-CD44 antibody RG7356 as an example. Thirteen patients with CD44-expressing solid tumors received 89Zr-labeled RG7356 after a variable dose of unlabeled antibody (0 to 675 mg). Tracer uptake in normal tissues (liver, spleen, kidney, lung, bone marrow and brain, blood pool) was used to calculate the area under the time antibody concentration curve (AUC).
Within the dose range of 1 to 450 mg tissue-to-blood AUC ratios decreased for the spleen, liver, bone marrow, lung and kidney, indicating dose-dependent uptake. This observation indicates target antigen expression in normal tissues, limiting the use of RG7356 for targeting toxic payloads to the tumor (e.g. antibody– drug conjugate approaches). This study demonstrates how immuno-PET in a dose escalation study provides a non-invasive technique to quantify dose-dependent uptake in normal tissues, indicating specific, target-mediated uptake. No focal tumor uptake was observed in the lowest dose cohorts (1-200 mg), suggesting insufficient supply of mAb for tumor targeting. In all patients receiving ≥ 450 mg (n=7) tumor uptake of the antibody was observed, suggesting antigen-mediated uptake. However, a different study design using two administrations of the tracer per patient (with a variable dose of unlabeled antibody), would be better suited to determine dose-dependency for tumors. Recently, an example of such a study design was reported to assess antigen-mediated specific tumor uptake for a 89Zr- labeled antiHER3 mAb (9).
89Zr-immuno-PET can be used to assess non-specific uptake in normal tissues
Currently, it is common practice to report the result of 89Zr-immuno-PET studies as SUV. However, this value represents the total PET signal and may contain a significant non-antigen mediated contribution. Quantification of non-specific uptake in normal tissues is the first critical step towards quantification of target- engagement in normal tissues and tumor with 89Zr-immuno-PET. This non- specific contribution in normal tissues is expected to be similar for a non-binding mAb and for mAbs without target expression in the respective tissue. Non-specific uptake is reversible (e.g. blood volume) or irreversible (due to 89Zr-residualization after mAb degradation).
In Chapter 9, non-specific uptake in normal tissues without known target expression was assessed for four 89Zr-labeled intact IgG1 antibodies (89Zr- antiCD20, 89Zr-antiEGFR, 89Zr-antiPSMA and 89Zr-antiHER2). Patlak graphical
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Summary and discussion
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