Page 187 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer
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                                Towards 89Zr-immuno-PET to measure target engagement of antibodies
Volume of Distribution (VT)
Values for VT per mAb are presented in Table 2. Non-specific, reversible uptake is reflected by baseline values for VT for tissues without target expression. For the kidney, liver, lung and spleen respectively, measured baseline values for VT were 0.20 (0.16-0.25), 0.24 (0.21-0.28), 0.09 (0.07-0.10) and 0.24 (0.20-0.27) mL×cm-3. For these tissues, the predicted values for VT (ABC + plasma volume fraction) were 0.19, 0.21, 0.10 and 0.25, respectively. No differences were observed between the measured baseline value for VT and the predicted value for kidney (p=0.24; n=25), liver (p= 0.07; n=9) and spleen (p=0.12; n=15). For lung, the measured baseline value for VT (0.09, 0.07-0.10) was statistically different (p< 0.02; n=25) from the predicted value of 0.10, but within the two-fold error range (0.05-0.20) of the predicted value.
Table 2 Volume of distribution Vt
  Kidney Liver Lung Spleen
89Zr-antiCD20 0.18(0.15-020) 0.24(0.21-0.28) 0.08(0.08-0.10) 0.20(0.18-0.21)
89Zr-antiEGFR 89Zr-antiPSMA 0.25(0.23-0.29) 0.28(0.21-0.32) 0.64(0.54-0.91) 0.29(0.23-0.43) 0.11(0.09-0.13) 0.07(0.06-0.09) 0.23(0.20-0.27) 0.22(0.20-0.28)
89Zr-antiHER2 Baseline 0.19(0.15-0.25) 0.20(0.16-0.25) 0.24(0.22-0.29) 0.24(0.21-0.28) 0.08(0.05-0.11) 0.09(0.07-0.10) 0.24(0.18-0.27) 0.24(0.20-0.27)
 Vt (mL×cm-3) presented as median (interquartile range)
Net Rate of Irreversible uptake (Ki)
Values for Ki per mAb are presented in Table 3. Non-specific, irreversible uptake is
reflected by baseline values for Ki for tissues without target expression. For kidney,
liver, lung and spleen respectively, measured baseline values for Ki were 0.7 (0.4-
1.3), 1.1 (0.8-2.1), 0.2 (0.1-0.3) and 0.5 (0.3-0.7) μL×g-1×h-1. For kidney, the
baseline catabolic rate was 0.23 mL×h-1, equal to 3% of the whole body catabolic
rate (predicted value 6%). Fractional catabolic rate of liver, lung and spleen were 9 30%, 3% and 1%, respectively (predicted values were 30%, 1.3% and 2.8%).
Detection of Target Engagement
In case of target engagement (Figure 1C), we expect to observe an increased rate of irreversible uptake compared to the baseline value. Expression of PSMA was reported for the kidney (18) and therefore target engagement of 89Zr-antiPSMA is expected in this tissue. Patlak linearization for 89Zr-antiPSMA was performed (Figure 3). In this case, a four-fold higher Ki (2.8 vs 0.7) was obtained compared to the baseline value for the kidney, indicating target engagement by irreversible
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