Therapeutic efficacy evaluation of radioimmunotherapy with 90 Y-labeled anti-podoplanin antibody NZ-12 for mesothelioma

Our plain-English summary of Therapeutic efficacy evaluation of radioimmunotherapy with 90 Y-labeled anti-podoplanin antibody NZ-12 for mesothelioma, by H. Sudo, A.B. Tsuji, A. Sugyo, et al (Cancer Science, 2019).

The study

• Authors: H. Sudo, A.B. Tsuji, A. Sugyo, T. Saga, M.K. Kaneko, Y. Kato, T. Higashi
• Journal: Cancer Science
• Published: 2019;110(5):1653-1664
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Podoplanin is a type I transmembrane sialomucin-like glycoprotein that is highly expressed in malignant mesothelioma. The rat-human chimeric antibody NZ-12 has high affinity for human podoplanin and antibody-dependent cellular cytotoxicity and is applicable for radioimmunotherapy (RIT) to enhance the antitumor effect. In the present study, we evaluated the in vivo and in vitro properties of radiolabeled NZ-12 and the antitumor effect of RIT with 90 Y-labeled NZ-12 in an NCI-H226 (H226) malignant mesothelioma xenograft mouse model. 111 In-labeled NZ-12 bound specifically to H226 cells with high affinity, and accumulation was high in H226 tumors but low in major organs. RIT with 90 Y-labeled NZ-12 significantly suppressed tumor growth and prolonged survival without body weight loss and obvious adverse effects. Higher podoplanin expression levels were observed in human mesothelioma specimens, suggesting higher tumor accumulation of 90 Y-labeled NZ-12 in patients compared with the H226 tumor xenografts. Our findings suggest that 90 Y-labeled NZ-12 is a promising RIT agent as a new therapeutic option for malignant mesothelioma that warrants further clinical studies to evaluate the dosimetry and efficacy in patients.

© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

In plain English

This was a laboratory and animal study testing an experimental treatment for malignant mesothelioma, not a study of asbestos exposure. The treatment, called radioimmunotherapy, attaches radioactive yttrium-90 to NZ-12, an antibody against a protein called podoplanin. The authors grew human mesothelioma cells (the H226 line) as tumors under the skin of male nude mice. Groups of 10 mice received unlabeled NZ-12, a radioactive comparison antibody that does not target podoplanin, or 1.85 or 3.70 MBq of yttrium-90-labeled NZ-12. The 3.70 MBq dose significantly suppressed tumor growth during the first 21 days, after which tumors grew again. These mice also took significantly longer than the other groups to reach a tumor volume of 500 cubic millimeters, the survival endpoint. The 1.85 MBq dose had no significant effect. Mice given the treatment showed no significant body weight loss. In 19 human mesothelioma tissue samples, 17 stained positive for podoplanin. The authors concluded that the treatment is a promising potential option for malignant mesothelioma. They noted that complete remission remains to be shown, that few human samples were tested, and that patient dosimetry studies are 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: Animal experiment (mouse tumor xenograft model) with laboratory cell studies and staining of a purchased human tissue array
• Who was studied: Male nude mice (6 weeks old) carrying tumors grown from the human mesothelioma cell line H226, 10 mice per treatment group. Also two mesothelioma cell lines in culture: H226 (podoplanin-positive) and 211H (podoplanin-negative). Also a tissue array of 19 human malignant mesothelioma cases: 13 epithelioid, 3 sarcomatoid and 3 mixed.
• Exposure: Not an asbestos exposure study. The treatment studied was the anti-podoplanin antibody NZ-12 labeled with yttrium-90, given intravenously at 1.85 or 3.70 MBq. Comparison groups received the unlabeled antibody or 3.70 MBq of a yttrium-90-labeled control antibody. Indium-111-labeled antibody was used to measure where the antibody went in the body. A separate group of tumors received external X-ray doses of 0, 25 or 50 Gy.
• Main results:
  • In cell experiments, indium-111-labeled NZ-12 bound to H226 cells, with a maximum of 34.5% plus or minus 1.0%. It did not bind to the podoplanin-negative 211H cells.
  • In tumor-bearing mice, tumor uptake of indium-111-labeled NZ-12 reached 23.2 plus or minus 0.9% of the injected dose per gram on day 7. Uptake of the control antibody ranged from 6.5 plus or minus 0.5% to 9.0 plus or minus 1.9%.
  • The estimated radiation dose absorbed by the H226 tumors at 3.70 MBq was 24.8 Gy for yttrium-90-labeled NZ-12 and 10.6 Gy for the control antibody. Among major organs the lungs received the highest dose: 14.4 Gy with NZ-12 and 15.9 Gy with the control antibody.
  • In treated mice, 3.70 MBq of yttrium-90-labeled NZ-12 significantly suppressed tumor growth during the first 21 days compared with the unlabeled antibody, after which tumors gradually grew again. The 1.85 MBq dose and the 3.70 MBq control antibody gave no significant suppression.
  • Mice in the 3.70 MBq NZ-12 group took significantly longer than the other groups to reach a tumor volume of 500 cubic millimeters, which the authors used as the endpoint of their survival analysis (p less than 0.01 against unlabeled NZ-12 and 1.85 MBq, p less than 0.05 against the control antibody). This endpoint was tumor size, not death.
  • Mice given yttrium-90-labeled NZ-12 showed no significant body weight loss and no visible adverse effects. Mice given the 3.70 MBq control antibody had a transient but significant weight loss during the first 7 days.
  • Tumors treated with 3.70 MBq of yttrium-90-labeled NZ-12 showed necrosis and fewer dividing cells (Ki-67 staining). The drop in dividing cells was statistically significant on days 3 and 7. Few dying cells were seen by TUNEL staining in any group.
  • Podoplanin staining was positive in 17 of 19 human mesothelioma samples (89.5%): 12 of 13 epithelioid, 2 of 3 sarcomatoid and 3 of 3 mixed. Staining tended to be stronger than in the H226 mouse tumors.
  • External X-ray doses of 25 and 50 Gy significantly reduced H226 tumor volumes compared with 0 Gy after an initial increase over the first 14 days. The 25 Gy dose corresponds to the estimated tumor dose from 3.70 MBq of yttrium-90-labeled NZ-12. The authors considered radioimmunotherapy less effective than external radiation at the corresponding dose in these tumors, noting that H226 is a radioresistant cell line.
• The authors' conclusion: The authors concluded that 3.70 MBq of yttrium-90-labeled NZ-12 significantly suppressed tumor growth without body weight loss in this mouse model. Given the higher podoplanin levels seen in human specimens, they described the treatment as a promising potential therapeutic option for malignant mesothelioma patients.
• Limitations the authors state:
  • The treatment delayed tumor growth, and further preclinical studies are needed to see whether complete remission can be achieved.
  • Only a small number of human mesothelioma specimens were analyzed for podoplanin.
  • Clinical studies are needed to measure radiation dosimetry in mesothelioma patients and so predict effect and safety.
  • How the antibody distributes in the body likely differs between mice and humans.

Topics

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

Medical terms in this study, explained in our Lexicon: Podoplanin (D2-40), Mesothelioma, Glycoprotein.

Related studies

• Antitumor effect of novel anti-podoplanin antibody NZ-12 against malignant pleural mesothelioma in an orthotopic xenograft model — S. Abe, M.K. Kaneko, et al. (2016)
• Establishment of Mouse Monoclonal Antibody LpMab-13 Against Human Podoplanin — S. Ogasawara, M.K. Kaneko, et al. (2016)
• Antitumor activity of chLpMab-2, a human-mouse chimeric cancer-specific antihuman podoplanin antibody, via antibody-dependent cellular cytotoxicity — M.K. Kaneko, S. Yamada, et al. (2017)
• Therapeutic antitumor efficacy of anti-epidermal growth factor receptor antibody, cetuximab, against malignant pleural mesothelioma — J. Kurai, H. Chikumi, et al. (2012)
• Podoplanin: An emerging cancer biomarker and therapeutic target — H. Krishnan, J. Rayes, et al. (2018)
• Antitumor activity of anti-C-ERC/mesothelin monoclonal antibody in vivo — K. Inami, M. Abe, et al. (2010)

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