Page 70 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

Chapter 4
obvious targeting of 89Zr-mAb U36 was observed in the skin. However, Tijink et al. reported a fatal adverse event due to skin toxicity after treatment with the ADC bivatuzumab mertansine, a humanized anti-CD44v6 mAb conjugated to a potent maytansine derivate (13). This toxicity profile, most probably due to expression of CD44v6 in the skin, was not predicted based on assessment of biodistribution of 89Zr-cmAbU36 as reported by Börjesson et al. (12). Among others, this may due to detection limitations of PET, inter-individual differences in target expression, or differences in biodistribution between the mAb and the ADC.
A technical aspect of this first 89Zr-immuno-PET study to be considered is the rationale for the total protein dose of cmAb U36 administered. This protein dose of 10 mg was chosen as previous studies observed that biodistribution was not mAb-dose dependent within the range of 2-52 mg (14-16).
Finally, good agreement was reported for image-derived quantification of blood pool radioactivity as well as tumor uptake of 89Zr-cmAb U36 compared to ex vivo radioactivity measurements in, respectively, venous blood samples and biopsies from surgical tumor resection. This is an important achievement in performance, showing accurate quantification of 89Zr-mAb with PET.
89Zr-labeled trastuzumab in breast cancer
Treatment with trastuzumab, which targets the human epidermal growth factor receptor 2 (HER2), has improved the prognosis for patients with HER2-positive breast cancer (17) and gastric cancer (18). HER2 is involved in cell survival, proliferation, cell maturation, metastasis, angiogenesis and has anti-apoptotic effects. It is also expressed in other malignancies, including ovarian and endometrial carcinoma, and in normal epithelial cells and hematopoietic cells (19). It is known that the extracellular domain of HER2 can enter the circulation after shedding from the surface of tumor cells (20).
Currently assessment of HER2 status is performed with immunohistochemistry (IHC) or fluorescent in situ hybridization on tumor biopsies. Some studies have shown up to 15% intra-individual heterogeneity in HER2 status between primary tumors and metastases (21) leading to the recommendation to repeat biopsies to assess HER2 status during the course of the disease. As some tumor lesions are inaccessible for biopsies and it is impossible to biopsy every tumor lesion to assess heterogeneity, there is a need for a non-invasive technique to assess whole body HER2 status for diagnosis, staging and to guide individualized treatment.
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