Page 170 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

Chapter 8
kidney, lung and brain. For the brain, a constant low tissue-to-blood AUC ratio was observed for all dose cohorts. Assuming that RG7356 does not cross the blood-brain-barrier, this value is determined by the blood volume fraction of the brain. For the spleen, liver, bone marrow, kidney and lung, dose-dependent uptake of 89Zr-RG7356 was observed, indicating target-antigen mediated specific uptake in these tissues. A very similar pattern of dose-dependent uptake in the spleen, liver and bone marrow has been reported previously in the preclinical study with 89Zr-RG7356 in cynomolgus monkeys, indicating that such preclinical immuno- PET studies can be predictive with respect to normal tissue uptake in human (9).
Target antigen expression in these tissues is a plausible explanation for dose-dependent uptake, as protein expression of CD44 has been reported for normal bone marrow, spleen, lung, kidney and liver (bile ducts) (16,17). Although dose-dependent uptake in tissues was observed, a constant tissue-to-blood AUC ratio was reached at 450 mg for all tissues, indicating target antigen saturation.
In addition, dose-independent uptake of the tracer in liver, spleen, bone marrow, kidney and lung was observed, indicating non-specific uptake. For the liver, based on a 30% blood volume fraction (18), a liver to blood AUC ratio of 0.3 would be expected. However, we observed a liver to blood AUC ratio of 0.85± 0.08 for the 675 mg dose cohort. The difference between the tissue-to-blood AUC ratio and blood volume fraction represents an additional accumulation mechanism in the liver, for example the large endothelial fenestrae or antibody catabolism. Stability of 89Zr-labeled antibodies, with minimal release of 89Zr, has been demonstrated in many in vitro and in vivo preclinical as well as clinical studies (11,19,20). There are no experimental data supporting accumulation of free 89Zr in normal tissues, except for the observation that free 89Zr, arising after internalisation and intracellular catabolism of the conjugate, may accumulate in bone tissue (not bone marrow) (19). However, in our study, we did not observe 89Zr accumulation in bone (Figure 2).
Although dose-dependent as well as dose-independent uptake in normal tissues was found in this imaging study, there were no safety concerns in the corresponding phase I dose escalation study, with treatment doses up to 1500 mg biweekly/2250 mg weekly. The overall safety profile of RG7356 was acceptable. Dose limiting toxicities included febrile neutropenia and aseptic meningitis (10). However, this phase I study was terminated at an early stage due to the lack of evidence of a clinical and/or pharmacodynamic (PD) dose-response relationship with RG7356.
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