Preclinical Evaluation of Podoplanin-Targeted Alpha-Radioimmunotherapy with the Novel Antibody NZ-16 for Malignant Mesothelioma

Our plain-English summary of Preclinical Evaluation of Podoplanin-Targeted Alpha-Radioimmunotherapy with the Novel Antibody NZ-16 for Malignant Mesothelioma, by H. Sudo, A.B. Tsuji, A. Sugyo, et al (Cells, 2021).

The study

• Authors: H. Sudo, A.B. Tsuji, A. Sugyo, M.K. Kaneko, Y. Kato, K. Nagatsu, H. Suzuki, T. Higashi
• Journal: Cells
• Published: 2021;10(10)
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Unlabelled: The prognosis of advanced mesothelioma is poor. Podoplanin (PDPN) is highly expressed in most malignant mesothelioma. This study aimed to evaluate the potential alpha-radioimmunotherapy (RIT) with a newly developed anti-PDPN antibody, NZ-16, compared with a previous antibody, NZ-12.

Methods: The in vitro properties of radiolabeled antibodies were evaluated by cell binding and competitive inhibition assays using PDPN-expressing H226 mesothelioma cells. The biodistribution of 111In-labeled antibodies was studied in tumor-bearing mice. The absorbed doses were estimated based on biodistribution data. Tumor volumes and body weights of mice treated with 90Y- and 225Ac-labeled NZ-16 were measured for 56 days. Histologic analysis was conducted.

Results: The radiolabeled NZ-16 specifically bound to H226 cells with higher affinity than NZ-12. The biodistribution studies showed higher tumor uptake of radiolabeled NZ-16 compared with NZ-12, providing higher absorbed doses to tumors. RIT with 225Ac- and 90Y-labeled NZ-16 had a significantly higher antitumor effect than RIT with 90Y-labeled NZ-12. 225Ac-labeled NZ-16 induced a larger amount of necrotic change and showed a tendency to suppress tumor volumes and prolonged survival than 90Y-labeled NZ-16. There is no obvious adverse effect.

Conclusions: Alpha-RIT with the newly developed NZ-16 is a promising therapeutic option for malignant mesothelioma.

In plain English

This was a laboratory and mouse study from Japan testing an experimental radiation treatment for malignant mesothelioma. It did not study asbestos exposure. The authors attached radioactive metals to NZ-16, a newly made antibody against podoplanin, and compared it with an earlier antibody, NZ-12. They used the H226 mesothelioma cell line and male nude mice with H226 tumors grown under the skin. NZ-16 bound the cells more strongly and reached higher tumor levels on day 4 (15.1 versus 10.0 percent of injected dose per gram). In groups of five mice, NZ-16 carrying yttrium-90 or actinium-225 slowed tumor growth compared with unlabeled NZ-16 alone. The higher actinium dose (18.5 kBq) controlled tumors better than yttrium-90. All actinium-treated mice and 60% of yttrium-treated mice were counted as surviving, meaning their tumors stayed under 300 mm3. That difference among treated groups was not statistically significant. Weight loss was temporary. Estimated bone marrow doses exceeded the human limit the authors cited. The authors concluded that actinium-labeled NZ-16 is a promising potential therapy, noting that no complete remission occurred and only one cell line was used.

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 (cell) and animal experiment
• Who was studied: The NCI-H226 (H226) human mesothelioma cell line, and 4-week-old male nude mice (BALB/c-nu/nu) with H226 tumors implanted under the skin. Groups had 4 to 5 mice for distribution studies, 5 per group for treatment, and 3 per time point for tissue analysis.
• Exposure: No asbestos exposure was studied. The treatments were single intravenous injections of anti-podoplanin antibody NZ-16: unlabeled (0 MBq), labeled with yttrium-90 (3.7 MBq), or labeled with actinium-225 (11.1 or 18.5 kBq). Indium-111-labeled NZ-12 and NZ-16 were used for distribution and dose estimates.
• Main results:
  • In cell binding tests, maximum binding at 10 million H226 cells was 29.6 plus or minus 3.7% for indium-111-labeled NZ-16 and 22.9 plus or minus 3.3% for NZ-12. NZ-16 binding was significantly higher (p less than 0.01).
  • Attaching the chelator DOTA weakened binding less for NZ-16 than for NZ-12. Estimated binding affinities were 1.7 nM (intact) and 5.7 nM (DOTA-conjugated) for NZ-12, and 1.8 nM and 2.7 nM for NZ-16.
  • In tumor-bearing mice on day 4, tumor uptake was 15.1 plus or minus 2.4% of injected dose per gram for indium-111-labeled NZ-16 and 10.0 plus or minus 0.4% for NZ-12 (p less than 0.01).
  • Estimated absorbed doses to tumors and most organs tended to be higher with NZ-16 than with NZ-12, but the difference was not statistically significant.
  • In mice given 3.7 MBq of yttrium-90-labeled NZ-16, tumors shrank from day 7 to day 21 after injection, then gradually grew again.
  • In mice given 18.5 kBq of actinium-225-labeled NZ-16, tumor growth was held back for 28 days and tumors then shrank until the end of observation. This was significantly different from both the unlabeled-antibody group and the yttrium-90 group (p less than 0.01).
  • Survival was defined by tumors staying under 300 mm3, not by death. At the end of observation, all mice given either actinium-225 dose counted as surviving, compared with 60% in the yttrium-90 group. All three radiolabeled treatments significantly prolonged survival compared with the 0 MBq groups (p less than 0.01).
  • Survival did not differ significantly among the three groups given radiolabeled antibodies.
  • Tumors treated with 18.5 kBq of actinium-225-labeled NZ-16 showed more dead (necrotic) areas on day 1 than yttrium-90-treated tumors. They showed extensive necrosis and lymphocyte infiltration by day 3.
  • Both yttrium-90 and actinium-225 treatment significantly reduced dividing (Ki-67-positive) tumor cells compared with unlabeled NZ-16 on days 1 to 7 (p less than 0.01).
  • All three radiolabeled treatments caused temporary weight loss that never exceeded 20%. No obvious damage was found in the spleen, kidney, liver, or bone marrow of treated mice.
  • Estimated bone marrow doses were 8.1 Sv for 3.7 MBq of yttrium-90-labeled NZ-16 and 7.0 Sv for 11.1 kBq of actinium-225-labeled NZ-16. The authors stated these exceed the limiting human dose of 4.5 Sv, so the dose given to patients would need to be lower.
• The authors' conclusion: The authors concluded that NZ-16 binds more strongly and reaches tumors better than NZ-12. They also concluded that actinium-225-labeled NZ-16 had a potent antitumor effect without obvious adverse effects in a mesothelioma mouse model, and is a promising potential therapeutic option for malignant mesothelioma patients.
• Limitations the authors state:
  • Actinium-225-labeled NZ-16 did not produce complete remission.
  • Dose estimates from mice cannot be applied directly to choosing doses for human patients.
  • Only one podoplanin-expressing mesothelioma cell line was used.
  • Because indium-111 was used as a stand-in to estimate actinium-225 doses, the actinium-225 doses could be underestimated.

Topics

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

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

Related studies

• Therapeutic efficacy evaluation of radioimmunotherapy with 90 Y-labeled anti-podoplanin antibody NZ-12 for mesothelioma — H. Sudo, A.B. Tsuji, et al. (2019)
• 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)
• Cancer-Specific Antihuman Podoplanin Antibody chLpMab-2f Exerts Antitumor Effects Against Pleural Mesothelioma — A. Yoshida, S. Abe, et al. (2026)
• Epitope Mapping of Monoclonal Antibody PMab-233 Against Tasmanian Devil Podoplanin — M. Sano, M.K. Kaneko, et al. (2019)
• Construction and Preclinical Evaluation of 211At Labeled Anti-mesothelin Antibodies as Potential Targeted Alpha Therapy Drugs — X. Wang, W. Ma, et al. (2020)

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