Page 161 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

89Zr-immuno-PET in a phase I trial INTRODUCTION
Treatment of cancer has improved as a result of immunotherapy with monoclonal antibodies (mAbs). Ideally, mAbs selectively target tumor cells, resulting in limited toxicity compared to classical chemotherapy.
However, lack of mAb selectivity may result in significant toxicity and/or suboptimal tumor targeting, leading to therapy failure. Therefore, it is important to confirm tumor selectivity of a novel candidate mAb to minimize toxicity and maximize efficacy, preferably in early stages of drug development. Currently, toxicity is assessed by dose escalation in traditional phase I trials, using dose limiting toxicity and a maximum tolerated dose to establish the therapeutic dose for the next stages of drug development (phase II and III trials). For the ideal mAb, selective tumor targeting is expected, with limited target antigen-mediated specific uptake in normal tissues.
Recently, there is increasing interest in the use of imaging techniques to measure the mAb biodistribution in vivo without requiring blood or tissue samples (1). After inert and stable radiolabeling, the radioactive mAb can be used to study the biodistribution of the non-radioactive mAb. According to this principle, positron emission tomography (PET) with 89Zr-labeled mAbs provides a non- invasive tool for in vivo visualization and quantification of mAbs (2-4).
Quantification of antibody accumulation in normal tissues and tumor
using PET imaging can be an important non-invasive tool to evaluate the
therapeutic potential of antibodies and antibody conjugates. For this purpose, target-mediated specific uptake is of interest. However, the measured PET signal 8 comprises non-specific uptake (dependent on the tissue blood volume fraction, as
well as other tissue characteristics, for example size of endothelial fenestrae by
which the antibody passes through the capillary wall) and potentially target antigen-mediated specific uptake. Differentiation between these specific and non-
specific contributions to the PET signal is possible, if we assume that they are dose-dependent and dose-independent, respectively (Figure 1). In this paper, we
present an experimental approach to assess specific uptake with immuno-PET in
a dose-escalation study, using RG7356 as an example.
Investigational RG7356 is an anti-CD44 recombinant humanized mAb, which targets the constant region of the extracellular domain of CD44 and provides antibody-dependent cellular phagocytosis of the malignant cells by macrophages (5). CD44 is a human cell-surface glycoprotein, which is expressed by several solid
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