Antigen targeting and anti-tumor activity of a novel anti-CD146 212Pb internalizing alpha-radioimmunoconjugate against malignant peritoneal mesothelioma

Our plain-English summary of Antigen targeting and anti-tumor activity of a novel anti-CD146 212Pb internalizing alpha-radioimmunoconjugate against malignant peritoneal mesothelioma, by K. Lindland, M.M. Malenge, R.G. Li, et al (Scientific Reports, 2024).

The study

• Authors: K. Lindland, M.M. Malenge, R.G. Li, R. Wouters, T.B. Bønsdorff, A. Juzeniene, S.M. Dragovic
• Journal: Scientific Reports
• Published: 2024;14(1):25941
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma, a highly aggressive cancer that primarily affects the serosal membranes, has limited therapeutic options, particularly for cavitary tumors, such as peritoneal and pleural malignant mesothelioma. Intracavitary administration of a radioimmunoconjugate to locally target mesothelioma cancer cells has been proposed as a treatment. CD146, upregulated in mesothelioma but not in healthy tissues, is a promising therapeutic target. This study characterized CD146 expression and binding/internalization kinetics of the CD146-targeting antibody OI-3 coupled with 212Pb (212Pb-TCMC-OI-3) in human mesothelioma cells. Flow cytometry showed that both chimeric (chOI-3) and murine (mOI-3) antibodies rapidly bound and internalized within 1-6 h in MSTO-211H cells. 212Pb-TCMC-chOI-3 exhibited 3.1- to 13.7-fold and 3.1- to 8.5-fold increased internalized 212Pb and 212Bi atoms per cell at 2 and 24 h, respectively, compared to isotype control, underscoring enhanced internalization efficiency. Intraperitoneal administration of 212Pb-TCMC-mOI-3 to mice with intraperitoneal MSTO-211H xenografts improved median survival by a ratio of 1.3 compared to non-binding 212Pb-TCMC-mIgG1. The ability of 212Pb-TCMC-mOI-3 to target and inhibit the growth of intraperitoneal mesothelioma xenografts supports targeted radionuclide therapy's efficacy for metastatic peritoneal mesothelioma. This study highlights the potential of localized CD146-targeted radioimmunotherapy for malignant mesothelioma, offering a new avenue for improving patient outcomes.

© 2024. The Author(s).

In plain English

This was a laboratory and animal study of an experimental radioactive treatment. It was not a study of people or of asbestos exposure. The authors attached radioactive lead-212 to an antibody called OI-3, which binds a protein called CD146 (the combined drug is called 212Pb-TCMC-OI-3). In two human cell lines the article calls mesothelioma lines, MSTO-211H and NCI-H226, a mouse form and a chimeric form of the antibody both bound CD146. In MSTO-211H cells the antibody was taken inside the cells, reaching 34.4% to 40.2% of the signal at 24 hours. In NCI-H226 cells this uptake was negligible. At 24 hours, the radioactive chimeric antibody put 13.7 times more lead-212 and 8.5 times more bismuth-212 inside MSTO-211H cells than a control antibody did. In 35 mice with mesothelioma cells growing in the abdomen, seven per group, mice given the radioactive mouse antibody had a median survival of 55 days. The other groups had median survivals of 39 to 42 days. The authors reported a statistically significant difference against saline and against unlabeled antibody. The authors concluded the treatment can improve survival in these mice and said toxicity studies are still needed.

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: Preclinical laboratory study (cell-line experiments) plus an animal experiment (survival study in mice with intraperitoneal mesothelioma xenografts)
• Who was studied: Two human cell lines, MSTO-211H and NCI-H226, described by the article as mesothelioma cell lines; and 35 female nude mice in Oslo, Norway, injected in the abdomen with MSTO-211H cells and randomized into five groups of seven
• Exposure: No asbestos exposure was studied. The intervention was the anti-CD146 antibody OI-3 (mouse form mOI-3 and chimeric form chOI-3) labeled with radioactive lead-212. In mice it was given into the abdomen at 348 kBq of 212Pb-TCMC-mOI-3 and compared with saline, unlabeled mOI-3, unlabeled mIgG, and 371 kBq of a non-binding radioactive control antibody (212Pb-TCMC-mIgG), with 10 µg of antibody per mouse.
• Main results:
  • The mOI-3, chOI-3 and ABX-MA1 antibodies bound specifically to CD146 on the MSTO-211H and NCI-H226 cell lines, and the chimeric antibody had a 2.8-fold higher affinity than the mouse antibody by SPR
  • In MSTO-211H cells, the internalized chOI-3 signal was 5.3 ± 2.6% at 1 h, 36.3 ± 14.0% at 6 h and 34.4 ± 5.4% at 24 h
  • In MSTO-211H cells, the internalized mOI-3 signal was 1.1 ± 0.2% at 1 h, 30.2 ± 0.6% at 6 h and 40.2 ± 3.2% at 24 h; differences between mOI-3 and chOI-3 were not statistically significant
  • In NCI-H226 cells, chOI-3 internalization was negligible: 4.5 ± 1.5% at 6 h and 8.3 ± 3.9% at 24 h
  • In MSTO-211H cells, compared with the control antibody 212Pb-TCMC-hIgG1, 212Pb-TCMC-chOI-3 gave a 3.1-fold (2 h) and 13.7-fold (24 h) increase in internalized lead-212 atoms per cell, and a 3.1-fold (2 h) and 8.5-fold (24 h) increase in internalized bismuth-212 atoms per cell
  • Mice given 212Pb-TCMC-mOI-3 had significantly longer survival than saline-treated mice (padj = 0.008) and unlabeled mOI-3 controls (padj = 0.01)
  • Median survival was 55 days in the 212Pb-TCMC-mOI-3 group; the article lists 40, 41, 39 and 42 days for the other groups, which it describes as 23–29% (13–16 days) shorter
  • Body weight did not differ significantly between any of the mouse groups
  • In normal (healthy) tissues from human, mouse and rat, OI-3 staining for CD146 was mostly weak to intermediate (+1 to +2 on a 0 to +3 scale), including in endothelial cells
• The authors' conclusion: The authors concluded that 212Pb-TCMC-OI-3 binds cell-surface targets, is taken into cells in the laboratory, and can improve survival in mice with intraperitoneal mesothelioma
• Limitations the authors state:
  • Full preclinical toxicity studies, including possible off-target effects on vascular tissues that express CD146, are still needed before use in patients
  • Whether giving the drug locally into the body cavity reduces whole-body toxicity has not been validated
  • Tumor size was not measured in the mice because the tumors were spread as scattered nodules
  • The radioactive internalization assay was not corrected for non-specific binding

Topics

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

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Mesothelioma, Median Overall Survival.

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