Page 14 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer
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                                Chapter 1
(tositumomab and ibritumomab-tiuxetan), antibody-drug conjugates (for example rituximab conjugated to doxorubicin) and bispecific mAbs (antiCD20xantiCD3 mAb).
When using the same target, in this case CD20, it is important to know whether the target antigen is still present and whether there is target engagement. Reduced CD20 expression has been associated with an inferior survival indeed (9). However, at relapsed/refractory disease, a biopsy is not always performed. Even when a biopsy is available, there are several limitations. Reduced CD20 expression cannot be reliably quantified by immunohistochemistry (IHC) (9). In addition, a single biopsy may not be representative due to sampling error and target expression may be heterogeneous. Therefore, even when CD20 expression is considered absent by IHC, it is still a matter of debate whether subsequent treatment with rituximab should be withheld.
This emphasizes the need for a reliable biomarker to predict which patients will benefit from rituximab treatment. Moreover, this would lead to improved cost effectiveness of the treatment, as rituximab is an expensive drug (10). For patients who are not likely to respond, different treatment approaches (e.g. aimed at different target antigens or other modalities) should be considered. In 2018, 33 mAbs have been approved by the FDA for the treatment of cancer (11). Ideally, mAbs provide selective treatment by targeting the tumor, without affecting normal tissues. For mAb-based treatments, the choice of a target antigen which is ‘available’ and tumor-selective is essential to increase chances of success (maximal efficacy, minimal toxicity). Assessment of target engagement in normal tissues should provide information which target is suitable for development of antibody-drug conjugates and help to improve safety. Preclinical studies provide limited information, as target expression in normal tissues may be different between animals and humans. Traditionally, in drug development, safety and dose finding is assessed in a first-in-human phase I dose escalation trial, followed by evaluation of preliminary efficacy in a phase II trial. If the results are promising late-stage trials in larger patient cohorts are performed, before the new drug is ready for regulatory review. Currently, many mAbs are under development for the treatment of cancer (phase 1 [200 mAbs], phase 2 [110 mAbs], late stage trials [33 mAbs]) (11). This process requires a considerable amount of time, effort, financial resources and large numbers of patients to participate in clinical trials. In general, the time from drug discovery to regulatory approval is estimated at 15 years, of which approximately 7 years in phase I to III trials (12).
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