A Novel PET Imaging Using⁶⁴Cu-Labeled Monoclonal Antibody against Mesothelin Commonly Expressed on Cancer Cells

Abstract

Mesothelin (MSLN) is a 40-kDa cell differentiation-associated glycoprotein appearing with carcinogenesis and is highly expressed in many human cancers, including the majority of pancreatic adenocarcinomas, ovarian cancers, and mesotheliomas, while its expression in normal tissue is limited to mesothelial cells lining the pleura, pericardium, and peritoneum. Clone 11-25 is a murine hybridoma secreting monoclonal antibody (mAb) against human MSLN. In this study, we applied the 11-25 mAb to in vivo imaging to detect MSLN-expressing tumors. In in vitro and ex vivo immunochemical studies, we demonstrated specificity of 11-25 mAb to membranous MSLN expressed on several pancreatic cancer cells. We showed the accumulation of Alexa Fluor 750-labeled 11-25 mAb in MSLN-expressing tumor xenografts in athymic nude mice. Then, 11-25 mAb was labeled with 64Cu via a chelating agent DOTA and was used in both in vitro cell binding assay and in vivo positron emission tomography (PET) imaging in the tumor-bearing mice. We confirmed that 64Cu-labeled 11-25 mAb highly accumulated in MSLN-expressing tumors as compared to MSLN-negative ones. The 64Cu-labeled 11-25 mAb is potentially useful as a PET probe capable of being used for wide range of tumors, rather than 18F-FDG that occasionally provides nonspecific accumulation into the inflammatory lesions.

Novel single‐chain variant of antibody against mesothelin established by phage library

“…In our previous PET imaging study, MSLN‐positive tumors in xenografts were visibly detected by 64 Cu‐radiolabeled full‐length mouse antihuman MSLN IgG, but it took 24‐48 hours to get fine contrast as a result of the long half‐life of IgG . In the present study, we established a scFv from a human‐origin gene sequence and rapid PET imaging (3 hours after the injection) of tumor regions was successfully demonstrated in xenografts using the scFv.…”

“…This indicates the potential of scFv H1a050 as a rapid PET probe for MSLN‐positive cancer diagnosis. The mouse antihuman MSLN 11‐25 IgG antibody we developed earlier was found to be useful for in vivo near infrared fluorescence (NIRF) imaging, and 64 Cu PET imaging . However, for PET imaging with 64 Cu‐DOTA‐11‐25 IgG, it took 24‐48 hours after the administration to obtain images with fine contrast.…”

Metastatic Heterogeneity of Breast Cancer: Companion and Theranostic Approach in Nuclear Medicine

“…A discrepancy between the primary tumor and the metastases was demonstrated in a non-invasive manner. Ulaner et al, have imaged primary HER2-negative tumors and HER2-positive secondary lesions with 89 Zr-trastuzumab. Hence, anti-HER2 led to significant tumor regression in these patients [55].…”

“…Several clinical studies have been conducted with trastuzumab, labeled with 64 Cu or 89 Zr, in patients with HER2-positive metastatic breast cancer [73,74]. A nanobody targeting HER2 has been labeled with 99m Tc and 68 Ga for SPECT and PET phenotypic imaging and with 177 Lu for radiotherapy.…”

“…Hence, several molecules are currently in clinical phases to evaluate the therapeutic performance of its targeting in tumors expressing mesothelin [96]. Among companion markers, some monoclonal antibodies and nanobodies have been evaluated in clinical and in preclinical models of breast cancers [89][90][91]. Once available in clinical practice, such agents will allow selecting patients eligible to all these therapies.…”