Page 86 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

Chapter 4
DMOT4039A, containing the MSLN-antibody MMOT0530A combined with the cytotoxic agent monomethyl auristatin E (43). For such an approach either the ADC itself can be labeled with 89Zr or the corresponding “naked” mAb, if available for human use. Labeling of the mAb part of the ADCs with 89Zr is well possible, but requires advanced analytical tools to prove that labeling is performed inertly. Assuming that both types of conjugates demonstrate similar biodistribution, which is a research question as such, PET imaging of the target will provide insight into drug distribution (tissue exposure, but also expression of the target and internalization of the antibody). Ideally, clinical 89Zr-immuno-PET studies with the “naked” mAb are performed before resources are put in the development of an ADC.
The aim of this imaging study was to assess biodistribution and tumor uptake, and the relationship between tumor uptake and MSLN expression, as well as response to treatment. Uptake in normal tissues was as expected, and did not indicate specific uptake, except for high hepatic uptake of 89Zr-MMOT0530A. This might be due to normal hepatic catabolism of the antibody, maybe slightly elevated by complex formation of the mAb with MSLN antigen shed into the circulation, as MSLN is not expressed on normal liver. Nevertheless, the uptake level in liver was similar to that of other antibodies such as trastuzumab and huJ591. Significant clinical toxicity, reported as dose limiting toxicity, were hypophosphatemia and hyperglycaemia and liver function abnormalities occurred in less than 10% of these patients. Tumor uptake of 89Zr-MMOT0530A was observed in 37 tumor lesions in 11 patients with pancreatic cancer and 4 patients with ovarian cancer, while 6 measurable tumor lesions visible on diagnostic CT in 4 patients were not detected by 89Zr-immuno-PET. Within patients a mean 2.4 ± 1.1-fold difference in uptake between tumor lesions was observed, indicating interlesional heterogeneity of tumor uptake.
Tumor uptake of 89Zr-MMOT0530A was correlated with MSLN expression levels determined with IHC scores (6 patients with pancreatic cancer and 4 patients with ovarian cancer). No correlation was found when the two tumor types were analyzed separately. Tumor uptake of 89Zr-MMOT0530A was not correlated with progression free survival, on both patient and lesion-based analysis.
The imaging dose for this study was considered to be sufficient, since the amount of tracer still present at 7 days p.i. was enough to clearly visualize the circulation. A first cohort of two patients received 37 MBq 89Zr-anti-MSLN (1 mg) and were imaged at days 2, 4 and 7 p.i.. Patients in the second cohort (n=10)
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