A novel PET imaging using ⁶⁴Cu-labeled monoclonal antibody against mesothelin commonly expressed on cancer cells

Our plain-English summary of A novel PET imaging using ⁶⁴Cu-labeled monoclonal antibody against mesothelin commonly expressed on cancer cells, by K. Kobayashi, T. Sasaki, F. Takenaka, et al (Journal of Immunology Research, 2015).

The study

• Authors: K. Kobayashi, T. Sasaki, F. Takenaka, H. Yakushiji, Y. Fujii, Y. Kishi, S. Kita, L. Shen, H. Kumon, E. Matsuura
• Journal: Journal of Immunology Research
• Published: 2015;2015:268172
• Cited by: 35 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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 (64)Cu 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 (64)Cu-labeled 11-25 mAb highly accumulated in MSLN-expressing tumors as compared to MSLN-negative ones. The (64)Cu-labeled 11-25 mAb is potentially useful as a PET probe capable of being used for wide range of tumors, rather than (18)F-FDG that occasionally provides nonspecific accumulation into the inflammatory lesions.

In plain English

This was a laboratory and animal study, not a study of asbestos exposure or of people. The authors tested whether a mouse antibody, 11-25, which binds mesothelin, a protein on many cancer cells, could show tumors on PET scans when labeled with radioactive copper-64. In cell cultures, mesothelin was released by two pancreatic cancer cell lines and by two cell lines the article calls lung mesothelioma cells. The antibody bound 50.9% of BxPC-3 cells and 31.4% of CFPAC-1 cells, but only 0.6% of PANC-1 cells. In male nude mice with human pancreatic cancer tumors, representative PET images showed the labeled antibody in the mesothelin-positive BxPC-3 and CFPAC-1 tumors but not the mesothelin-negative PANC-1 tumor. Tissue measurements showed significantly higher uptake in the positive tumors than in PANC-1. It also collected in the blood and liver. The authors noted that it cleared slowly from the blood and that tumor-to-blood ratios were no more than 1. No mesothelioma tumors were scanned in mice. The authors concluded that the labeled antibody significantly accumulated in mesothelin-expressing tumors compared with the mesothelin-negative tumor.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (cell culture) and animal experiment testing an antibody-based PET imaging probe
• Who was studied: Human cancer cell lines: pancreatic BxPC-3, CFPAC-1 and PANC-1; lung NCI-H226, MSTO-211H and NCI-H520; and epidermoid A-431. Also male BALB/c nude mice carrying human pancreatic cancer tumors (BxPC-3, CFPAC-1, PANC-1), studied at Okayama University, Japan.
• Exposure: No asbestos exposure was studied. Mice were injected with the anti-mesothelin antibody 11-25 labeled either with a fluorescent dye (Alexa Fluor 750) or with copper-64 (about 11 MBq). A control antibody (anti-KLH) was used for comparison.
• Main results:
  • Soluble mesothelin was found in the culture media of the pancreatic adenocarcinoma lines CFPAC-1 (57.9 ng/mL) and BxPC-3 (72.6 ng/mL). It was also found for the lines the article calls lung mesothelioma cells, MSTO-211H (71.6 ng/mL) and NCI-H226 (23.7 ng/mL). PANC-1 and NCI-H520 were at 0.0 ng/mL.
  • In flow cytometry, the 11-25 antibody reacted with 50.9% of BxPC-3 cells, 31.4% of CFPAC-1 cells, 0.6% of PANC-1 cells and 4.4% of A-431 cells.
  • After copper-64 labeling, the antibody's binding signal to mesothelin was 66.0% of that of the unlabeled antibody (at 1000 ng/mL). Its binding constant on live BxPC-3 cells was 353 plus or minus 63 nM.
  • On representative PET images of mice, the copper-64-labeled antibody was seen in the BxPC-3 tumor but not in the PANC-1 tumor. High accumulation was seen in the CFPAC-1 tumor at 24 and 48 hours.
  • In tissue (biodistribution) measurements, uptake of the 11-25 antibody was significantly higher in BxPC-3 and CFPAC-1 tumors than in PANC-1 tumors. This was lower uptake in PANC-1, not absent uptake.
  • In tissue measurements, accumulation of the 11-25 antibody was significantly higher than that of the control antibody in CFPAC-1 tumors at both time points (24 and 48 hours), and in BxPC-3 tumors at 48 hours.
  • At 24 and 48 hours, tumor-to-blood and tumor-to-muscle ratios of the 11-25 antibody were significantly higher in BxPC-3 and CFPAC-1 tumors than in PANC-1 tumors.
  • Relatively high accumulation of the labeled antibody was also seen in the blood and liver of the mice.
• The authors' conclusion: The authors concluded that the copper-64-labeled 11-25 antibody significantly accumulated in mesothelin-expressing tumors compared with the mesothelin-negative tumor, based on PET imaging and tissue measurements in mice.
• Limitations the authors state:
  • The labeled antibody cleared very slowly from the blood.
  • Tumor-to-blood ratios were no more than 1.
  • Part of the uptake in the larger CFPAC-1 tumor was probably nonspecific.
  • Because of copper-64's short half-life, tissue distribution was examined only at 24 and 48 hours.
  • The chelating agent used (DOTA) does not form a very stable complex with copper-64.

Topics

Medical terms in this study, explained in our Lexicon: Monoclonal Antibody, Mesothelin, Glycoprotein, Carcinogenesis, Adenocarcinoma, Ovarian Cancer, Mesothelioma, Mesothelial Cells.

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• Inhibition of mesothelin-CA-125 interaction in patients with mesothelioma by the anti-mesothelin monoclonal antibody MORAb-009: Implications for cancer therapy — R. Hassan, C. Schweizer, et al. (2010)
• A multifunctional mesothelin antibody-tagged microparticle targets human mesotheliomas — S.L. Macura, J.M. Hillegass, et al. (2012)
• Targeting a membrane-proximal epitope on mesothelin increases the tumoricidal activity of a bispecific antibody blocking CD47 on mesothelin-positive tumors — E. Hatterer, X. Chauchet, et al. (2020)

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