Page 67 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer
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                                Initial clinical trials with 89Zr-immuno-PET in oncology
INTRODUCTION
In recent years, monoclonal antibodies (mAbs) have become widely used for
treatment of cancer. Immunotherapy with mAbs aims for specific targeting and
therefore less toxicity compared to chemotherapy. Some mAbs have resulted in a
significant improvement of survival, for example the anti-CD20 antibody
rituximab for B cell lymphoma (1). However, not all patients benefit from mAb
treatment. Monotherapy with the anti-epidermal growth factor receptor (EGFR)
antibody cetuximab results in clinical benefit for half of the patients with advanced
colorectal cancer (without relevant gene mutations; RAS wild type) (2). 4
Next generation mAbs are aiming for increased potency, for example antibody-drug conjugates (ADC’s), mAbs capable of inhibiting immune checkpoints and multi-specific mAbs recognizing at least two different targets (3- 5). The number of novel targeted treatment options increases, however drug development requires time, efforts and significant resources. In addition, investigational drugs are evaluated in large patient cohorts before successful introduction in routine clinical care.
Improving response rates by quickly selecting the right drug for the right patient is paramount to reducing unnecessary toxicity and costs. In order to obtain clinical benefit from mAb treatment, the target antigen should be expressed in the tumor and the drug is required to reach and bind to the target (tumor targeting). Absence of target expression on normal tissue is important to limit toxicity of treatment.
Molecular imaging with 89Zr-labeled mAbs, also known as 89Zr-immuno- PET, provides a potential imaging biomarker to evaluate tumor targeting of mAbs. This technique is non-invasive and provides whole body information on both target expression and tumor targeting, as opposed to immunohistochemistry on a single biopsy, which only provides information on target expression. Prediction of efficacy and toxicity of mAb treatment by molecular imaging may be used to select individual patients for a treatment, or to select promising candidate drugs in drug development.
89Zr-immuno-PET allows visualization and quantification of biodistribution and tumor uptake (6). 89Zr is considered a suitable radioisotope for this purpose, due to its relatively long half-life (t1⁄2 = 78.4 hours), which corresponds with the time a mAb needs to reach the target. The use of 89Zr as a radiolabel and the coupling of 89Zr to mAbs, under Good Manufacturing Practice conditions, have
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