Page 180 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

Chapter 9
Non-specific uptake is due to the blood volume fraction of the tissue, as well as antibody distribution (entering the tissue interstitium through paracellular pores, and through endothelial cells mediated by the neonatal Fc-receptor, leaving the tissue by convective transport through lymph flow) (Figure 1A)(8). At equilibrium, this physiological component is linear with the plasma concentration (9) and is characterized as reversible uptake. In addition, non-specific catabolism of antibodies occurs by pinocytosis (e.g. in endothelial cells) and subsequent lysosomal proteolytic degradation (10,11). After the antibody is degraded, 89Zr residualizes, leading to another component of non-specific uptake (Figure 1B) (11,12,13). This component is proportional to the area under the plasma time activity curve from the time of injection up to the scan time point, and is characterized as irreversible uptake. For tissues without target expression, this uptake is solely due to residualization of 89Zr after non-target-mediated degradation of the mAb.
These two components of non-specific uptake can be quantified using graphical evaluation of transfer constants, commonly known as the ‘Patlak linearization’ approach as used for 18F-FDG-PET (14). For tissues without target expression, we expect transfer constants in agreement with known literature for non-binding mAbs. For tissues with target expression, transfer constants would potentially differ due to target engagement (Figure 1C)(15).
MATERIALS AND METHODS
Data collection
89Zr-immuno PET scans and blood sample data were obtained for 89Zr- obinutuzumab (16), 89Zr-cetuximab (17), 89Zr-huJ591 (18) and 89Zr-trastuzumab (19)(Table 1). In the remainder of this report, the 89Zr-labeled-mAbs used in these studies will be denoted as 89Zr-antiCD20, 89Zr-antiEGFR, 89Zr-antiPSMA and 89Zr- antiHER2, respectively. Data were selected based on the availability of scans at multiple time points (at least 3) for each patient, including plasma or serum activity concentrations from venous blood sampled at each scan time point.
Data was collected from 1) Amsterdam UMC, the Netherlands, 2) CHU Lille, France and 3) Memorial Sloan Kettering Cancer Center (MSKCC), USA. All studies were approved by an institutional review board and ethics committee. At CHU Lille and MSKCC, PET scans were acquired on a GE Discovery PET/CT
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