HER1-targeted 86Y-panitumumab possesses superior targeting characteristics than 86Y-cetuximab for PET imaging of human malignant mesothelioma tumors xenografts

Our plain-English summary of HER1-targeted 86Y-panitumumab possesses superior targeting characteristics than 86Y-cetuximab for PET imaging of human malignant mesothelioma tumors xenografts, by T.K. Nayak, K. Garmestani, D.E. Milenic, et al (PloS One, 2011).

The study

• Authors: T.K. Nayak, K. Garmestani, D.E. Milenic, K.E. Baidoo, M.W. Brechbiel
• Journal: PloS One
• Published: 2011;6(3):e18198
• Cited by: 45 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Unlabelled: Malignant mesothelioma (MM), a rare form of cancer is often associated with previous exposure to fibrous minerals, such as asbestos. Asbestos exposure increases HER1-activity and expression in pre-clinical models. Additionally, HER1 over-expression is observed in the majority of MM cases. In this study, the utility of HER1-targeted chimeric IgG(1), cetuximab, and a human IgG(2), panitumumab, radiolabeled with (86)Y, were evaluated for PET imaging to detect MM non-invasively in vivo, and to select an antibody candidate for radioimmunotherapy (RIT).

Methods: Radioimmunoconjugates (RICs) of cetuximab and panitumumab were prepared by conjugation with CHX-A''-DTPA followed by radiolabeling with (86)Y. The HER1 expression of NCI-H226, NCI-H2052, NCI-H2452 and MSTO-211H human mesothelioma cells was characterized by flow cytometry. In vivo biodistribution, pharmacokinetic analysis, and PET imaging were performed in tumor bearing athymic mice.

Results: In vivo studies demonstrated high HER1 tumor uptake of both RICs. Significant reduction in tumor uptake was observed in mice co-injected with excess mAb (0.1 mg), demonstrating that uptake in the tumor was receptor specific. Significant differences were observed in the in vivo characteristics of the RICs. The blood clearance T(½)α of (86)Y-cetuximab (0.9-1.1 h) was faster than (86)Y-panitumumab (2.6-3.1 h). Also, the tumor area under the curve (AUC) to liver AUC ratios of (86)Y-panitumumab were 1.5 to 2.5 times greater than (86)Y-cetuximab as observed by the differences in PET tumor to background ratios, which could be critical when imaging orthotopic tumors and concerns regarding radiation doses to normal organs such as the liver.

Conclusion: This study demonstrates the more favorable HER1-targeting characteristics of (86)Y-panitumumab than (86)Y-cetuximab for non-invasive assessment of the HER1 status of MM by PET imaging. Due to lower liver uptake, panitumumab based immunoconjugates may fare better in therapy than corresponding cetuximab based immunoconjugates.

In plain English

This was a laboratory and animal study. It did not study asbestos exposure in people. The authors compared two antibodies that attach to a protein called HER1, cetuximab and panitumumab. Each carried the radioactive tracer yttrium-86 for PET scanning. They measured HER1 on four human mesothelioma cell lines, then injected the antibodies into female athymic mice with tumors grown from three of those lines. Both antibodies collected in the tumors, which were visible on PET from 0.5 to 3 days after injection. Adding extra untagged antibody significantly reduced tumor uptake. In the first phase of clearance, tagged cetuximab left the blood faster than tagged panitumumab (half-lives of 0.9 to 1.1 hours versus 2.6 to 3.1 hours), and it built up more in the liver. Comparing tumor uptake with liver uptake accumulated over four days, panitumumab's ratios were 1.7, 2.5 and 1.4 times cetuximab's in the three tumor models. The authors concluded that tagged panitumumab had more favorable targeting characteristics for PET imaging of mesothelioma. They also suggested that panitumumab carrying yttrium-90 may be a better candidate for future radioimmunotherapy, which this study did not test.

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: Pre-clinical laboratory study: cell-line testing plus animal experiments (biodistribution, pharmacokinetics and PET imaging in mice with human mesothelioma tumor xenografts). No therapy was tested.
• Who was studied: Four human mesothelioma cell lines (NCI-H226, NCI-H2052, NCI-H2452, MSTO-211H) bought from the American Type Culture Collection. Female athymic nu/nu mice aged 5 to 8 weeks were given tumors from three of the lines (MSTO-211H, NCI-H226, NCI-H2052). There were at least four animals per group for biodistribution and at least three per group for PET, at the National Cancer Institute, Bethesda. Study dates are not given.
• Exposure: No asbestos or fiber exposure was studied. Mice were injected intravenously with the HER1-targeting antibodies cetuximab or panitumumab labeled with yttrium-86 (86Y-CHX-A''-DTPA conjugates). Some mice were co-injected with 0.1 mg of excess unlabeled antibody to test whether uptake was receptor-specific.
• Main results:
  • In the cell lines, HER1 levels varied: NCI-H226 had the highest mean fluorescence intensity and NCI-H2452 the lowest. The two antibodies bound comparably to each cell type.
  • Tumors in mice were clearly seen on PET from 0.5 to 3 days after injection of either labeled antibody.
  • Co-injecting 0.1 mg of unlabeled antibody significantly lowered tumor uptake for each tumor type and both antibodies. The authors took this to show the uptake was HER1 receptor-specific.
  • The first-phase (alpha) blood half-life of labeled panitumumab was significantly slower than that of labeled cetuximab. Table 2 gives 3.1, 3.0 and 2.6 h for panitumumab and 0.9, 1.1 and 0.9 h for cetuximab across the three tumor models. There was no significant difference in the second (beta) phase.
  • In every tumor model, liver exposure over 4 days (liver AUC) was significantly greater for labeled cetuximab than for labeled panitumumab. Table 2 gives 35.1, 40.6 and 40.7 for cetuximab versus 24.2, 18.2 and 29.7 for panitumumab, in percent injected dose times days per gram.
  • The ratio of tumor area under the curve to liver area under the curve over 0 to 4 days was 1.7, 2.5 and 1.4 times higher for labeled panitumumab than for labeled cetuximab in mice with NCI-H226, MSTO-211H and NCI-H2052 tumors, respectively. These are ratios of uptake accumulated over four days, not values from a single scan.
  • Blood AUC values were slightly higher for panitumumab than for cetuximab, but the difference was not statistically significant.
  • In NCI-H226 tumor-bearing mice, tumor uptake rose over 4 days for both antibodies, while blood activity fell.
  • From these imaging data, the authors suggested that panitumumab labeled with the therapeutic radionuclide yttrium-90 may be a more favorable candidate than yttrium-90-labeled cetuximab for future radioimmunotherapy, because of lower expected liver radiation doses. This therapy was not tested in the study.
• The authors' conclusion: The authors concluded that 86Y-labeled panitumumab showed more favorable HER1-targeting characteristics than 86Y-labeled cetuximab for non-invasive staging and HER1 assessment of mesothelioma by PET. They stated that targeting HER1 for imaging and radionuclide therapy warrants further investigation.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Cetuximab (Erbitux), Malignant Mesothelioma, Asbestos Exposure, Mesothelioma.

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