Pet-Imaging with 89Zr-Labeled Anti-Mesothelin (Msln) Antibody in Patients with Pancreatic Cancer (Pc) or Ovarian Cancer (Oc)

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Aim: The tumor antigen MSLN is frequently overexpressed in PC and OC. A 89Zr-PET study (NCT01832116) with MMOT0530A, an anti-MSLN antibody, was initiated in conjunction with a phase 1 study of the antibody-drug conjugate DMOT4039A (containing MMOT0530A linked to the anti-mitotic agent MMAE, NCT01469793). This imaging study aims to investigate antibody tumor uptake, whole body distribution and organ pharmacokinetics and to explore the relation between uptake and MSLN expression and response to DMOT40392A treatment in patients with unresectable PC or platinum-resistant OC. Methods: Before receiving DMOT4039A, patients were injected with 37 MBq 89Zr-MMOT0530A +/- additional unlabeled MMOT0530A, followed by PET/CT imaging 2, 4 and 7 days post injection (pi). Tracer uptake was quantified with standardized uptake value (SUV) and expressed as mean (±SD). MSLN expression was determined in archival tumor tissue with an exploratory immunohistochemical (IHC) assay. Results: 7 PC and 4 OC patients were included. MSLN expression varied from 0 to 3+. The optimal antibody protein dose resulting in sufficient circulating tracer was 10 mg MMOT0530A and the optimal imaging time was 4 or 7 days pi. Tumor tracer uptake was observed in 37 quantifiable tumor lesions (all patients) with mean SUV of 10.7 (±6.3) on PET 4 days pi. The mean SUV per patient (1-8 lesions/patient) was 10.9 (±5.7), with 9.2 (±4.5) in PC and 11.9 (±7.4) in OC lesions on PET 4 days pi. Within patients, a mean 2.4-fold (±1.10) difference in tumor uptake between lesions was found. Two measurable lesions on diagnostic CT (according to RECIST 1.1) were not visible on PET. Uptake in blood, liver, kidneys, spleen and intestine reflected normal antibody distribution with mean SUV at day 4 pi of 5.6, 7.8, 6.1, 4.1 and 3.2, respectively, while low uptake was observed in muscle, lung, brain and bone (0.6, 1.0, 0.2 and 0.7, respectively). Tracer tumor uptake was lower in the 2 patients with IHC scores 0 and 1. Best response on DMOT4039A was stable disease in ten patients. An association between iPET tumor uptake and clinical response could not be determined. Conclusions: 89Zr-MMOT0530A-PET shows antibody uptake in primary and metastatic PC and OC tumor lesions. This technique can potentially guide antibody-based therapy development.