{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:21:22Z","timestamp":1772252482313,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T00:00:00Z","timestamp":1632268800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18K07778"],"award-info":[{"award-number":["18K07778"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K07688"],"award-info":[{"award-number":["21K07688"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K07230"],"award-info":[{"award-number":["21K07230"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18H02774"],"award-info":[{"award-number":["18H02774"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K07168"],"award-info":[{"award-number":["21K07168"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K07705"],"award-info":[{"award-number":["19K07705"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21am0401013"],"award-info":[{"award-number":["JP21am0401013"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21am0101078"],"award-info":[{"award-number":["JP21am0101078"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cells10102503","type":"journal-article","created":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T09:14:57Z","timestamp":1632302097000},"page":"2503","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Preclinical Evaluation of Podoplanin-Targeted Alpha-Radioimmunotherapy with the Novel Antibody NZ-16 for Malignant Mesothelioma"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5012-6435","authenticated-orcid":false,"given":"Hitomi","family":"Sudo","sequence":"first","affiliation":[{"name":"Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science (iQMS), National Institutes for Quantum and Radiological Science and Technology (QST), 4-9-1 Anagawa, Inage, Chiba 263-8555, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2726-288X","authenticated-orcid":false,"given":"Atsushi B.","family":"Tsuji","sequence":"additional","affiliation":[{"name":"Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science (iQMS), National Institutes for Quantum and Radiological Science and Technology (QST), 4-9-1 Anagawa, Inage, Chiba 263-8555, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aya","family":"Sugyo","sequence":"additional","affiliation":[{"name":"Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science (iQMS), National Institutes for Quantum and Radiological Science and Technology (QST), 4-9-1 Anagawa, Inage, Chiba 263-8555, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mika K.","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5385-8201","authenticated-orcid":false,"given":"Yukinari","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan"},{"name":"Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kotaro","family":"Nagatsu","sequence":"additional","affiliation":[{"name":"Department of Advanced Nuclear Medicine Science, Institute for Quantum Medical Science (iQMS), National Institutes for Quantum and Radiological Science and Technology (QST), 4-9-1 Anagawa, Inage, Chiba 263-8555, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hisashi","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Advanced Nuclear Medicine Science, Institute for Quantum Medical Science (iQMS), National Institutes for Quantum and Radiological Science and Technology (QST), 4-9-1 Anagawa, Inage, Chiba 263-8555, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuya","family":"Higashi","sequence":"additional","affiliation":[{"name":"Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science (iQMS), National Institutes for Quantum and Radiological Science and Technology (QST), 4-9-1 Anagawa, Inage, Chiba 263-8555, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1056\/NEJMra050152","article-title":"Advances in malignant mesothelioma","volume":"353","author":"Robinson","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1200\/JCO.2017.76.6394","article-title":"Treatment of Malignant Pleural Mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline","volume":"36","author":"Kindler","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.5858\/2005-129-1407-IDOEMA","article-title":"Immunohistochemical diagnosis of epithelioid mesothelioma: An update","volume":"129","author":"Ordonez","year":"2005","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1111\/j.1440-1843.2005.00714.x","article-title":"Advances in the diagnosis, evaluation, and management of malignant pleural mesothelioma","volume":"10","author":"Sterman","year":"2005","journal-title":"Respirology"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Nishinaga, Y., Sato, K., Yasui, H., Taki, S., Takahashi, K., Shimizu, M., Endo, R., Koike, C., Kuramoto, N., and Nakamura, S. (2020). Targeted Phototherapy for Malignant Pleural Mesothelioma: Near-Infrared Photoimmunotherapy Targeting Podoplanin. Cells, 9.","DOI":"10.3390\/cells9041019"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1111\/cas.13979","article-title":"Therapeutic efficacy evaluation of radioimmunotherapy with 90Y-labeled anti-podoplanin antibody NZ-12 for mesothelioma","volume":"110","author":"Sudo","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Quintanilla, M., Montero-Montero, L., Renart, J., and Mart\u00edn-Villar, E. (2019). Podoplanin in Inflammation and Cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030707"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/cncr.22061","article-title":"Overexpression of podoplanin in oral cancer and its association with poor clinical outcome","volume":"107","author":"Yuan","year":"2006","journal-title":"Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1007\/s00401-006-0063-y","article-title":"Increased expression of podoplanin in malignant astrocytic tumors as a novel molecular marker of malignant progression","volume":"111","author":"Mishima","year":"2006","journal-title":"Acta Neuropathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1730","DOI":"10.1182\/blood-2007-11-124693","article-title":"Tetraspanin family member CD9 inhibits Aggrus\/podoplanin-induced platelet aggregation and suppresses pulmonary metastasis","volume":"112","author":"Nakazawa","year":"2008","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1002\/ijc.27919","article-title":"Recombinant anti-podoplanin (NZ-1) immunotoxin for the treatment of malignant brain tumors","volume":"132","author":"Chandramohan","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6239","DOI":"10.4049\/jimmunol.1300448","article-title":"A novel targeting therapy of malignant mesothelioma using anti-podoplanin antibody","volume":"190","author":"Abe","year":"2013","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/nrc3925","article-title":"Radioimmunotherapy of human tumours","volume":"15","author":"Larson","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Gudkov, S.V., Shilyagina, N.Y., Vodeneev, V.A., and Zvyagin, A.V. (2016). Targeted Radionuclide Therapy of Human Tumors. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17010033"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.2967\/jnumed.116.178673","article-title":"225Ac-PSMA-617 for PSMA-Targeted alpha-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer","volume":"57","author":"Kratochwil","year":"2016","journal-title":"J. Nucl. Med."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Tafreshi, N.K., Doligalski, M.L., Tichacek, C.J., Pandya, D.N., Budzevich, M.M., El-Haddad, G., Khushalani, N.I., Moros, E.G., McLaughlin, M.L., and Wadas, T.J. (2019). Development of Targeted Alpha Particle Therapy for Solid Tumors. Molecules, 24.","DOI":"10.3390\/molecules24234314"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1016\/j.addr.2008.04.009","article-title":"Realizing the potential of the Actinium-225 radionuclide generator in targeted alpha particle therapy applications","volume":"60","author":"Miederer","year":"2008","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1089\/mab.2016.0047","article-title":"Chimeric Anti-Human Podoplanin Antibody NZ-12 of Lambda Light Chain Exerts Higher Antibody-Dependent Cellular Cytotoxicity and Complement-Dependent Cytotoxicity Compared with NZ-8 of Kappa Light Chain","volume":"36","author":"Kaneko","year":"2017","journal-title":"Monoclon. Antib. Immunodiagn. Immunother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1016\/j.bbrc.2006.08.171","article-title":"Inhibition of tumor cell-induced platelet aggregation using a novel anti-podoplanin antibody reacting with its platelet-aggregation-stimulating domain","volume":"349","author":"Kato","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.2967\/jnumed.114.138347","article-title":"Efficient 1-step radiolabeling of monoclonal antibodies to high specific activity with 225Ac for alpha-particle radioimmunotherapy of cancer","volume":"55","author":"Maguire","year":"2014","journal-title":"J. Nucl. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Yoshida, C., Tsuji, A.B., Sudo, H., Sugyo, A., Kikuchi, T., Koizumi, M., Arano, Y., and Saga, T. (2013). Therapeutic efficacy of c-kit-targeted radioimmunotherapy using 90Y-labeled anti-c-kit antibodies in a mouse model of small cell lung cancer. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0059248"},{"key":"ref_22","unstructured":"Eckerman, K.F., and Endo, A. (2007). MIRD Radionuclide Data and Decay Schemes, Society of Nuclear Medicine. [2nd ed.]."},{"key":"ref_23","first-page":"3031s","article-title":"Studies on the red marrow dosimetry in radioimmunotherapy: An experimental investigation of factors influencing the radiation-induced myelotoxicity in therapy with beta-, Auger\/conversion electron-, or alpha-emitters","volume":"5","author":"Behr","year":"1999","journal-title":"Clin. Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"311","DOI":"10.2967\/jnumed.108.058651","article-title":"MIRD Pamphlet No. 22 (Abridged): Radiobiology and Dosimetry of \u03b1-Particle Emitters for Targeted Radionuclide Therapy","volume":"51","author":"Sgouros","year":"2010","journal-title":"J. Nucl. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1159\/000086952","article-title":"Enhanced expression of Aggrus (T1alpha\/podoplanin), a platelet-aggregation-inducing factor in lung squamous cell carcinoma","volume":"26","author":"Kato","year":"2005","journal-title":"Tumour. Biol."},{"key":"ref_26","first-page":"599","article-title":"High-level expression of podoplanin in benign and malignant soft tissue tumors: Immunohistochemical and quantitative real-time RT-PCR analysis","volume":"25","author":"Xu","year":"2011","journal-title":"Oncol. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8552","DOI":"10.1038\/sj.onc.1207869","article-title":"Aggrus: A diagnostic marker that distinguishes seminoma from embryonal carcinoma in testicular germ cell tumors","volume":"23","author":"Kato","year":"2004","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1007\/s00259-017-3919-6","article-title":"Antitumor effects of radionuclide treatment using alpha-emitting meta-211At-astato-benzylguanidine in a PC12 pheochromocytoma model","volume":"45","author":"Ohshima","year":"2018","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1007\/s00259-011-1903-0","article-title":"Pretargeted radioimmunotherapy of colorectal cancer metastases: Models and pharmacokinetics predict influence of the physical and radiochemical properties of the radionuclide","volume":"38","author":"Frampas","year":"2011","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1007\/s12094-020-02532-2","article-title":"SEOM clinical guidelines for the treatment of malignant pleural mesothelioma (2020)","volume":"23","author":"Nadal","year":"2021","journal-title":"Clin. Transl. Oncol."},{"key":"ref_31","first-page":"123","article-title":"Tolerance of Normal Tissue to Therapeutic Radiation","volume":"1","author":"Emami","year":"2013","journal-title":"Rep. Radiother. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s13550-017-0303-2","article-title":"Pharmacokinetics, microscale distribution, and dosimetry of alpha-emitter-labeled anti-PD-L1 antibodies in an immune competent transgenic breast cancer model","volume":"7","author":"Nedrow","year":"2017","journal-title":"EJNMMI Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S53","DOI":"10.1016\/j.jmir.2019.05.008","article-title":"Targeted Alpha-Particle Therapy for Hematologic Malignancies","volume":"50","author":"Jurcic","year":"2019","journal-title":"J. Med. Imaging Radiat. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.radonc.2016.10.007","article-title":"Radiosensitization of non-small-cell lung cancer cells and xenografts by the interactive effects of pemetrexed and methoxyamine","volume":"121","author":"Oleinick","year":"2016","journal-title":"Radiother. Oncol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/10\/2503\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:03:03Z","timestamp":1760166183000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/10\/2503"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,22]]},"references-count":34,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["cells10102503"],"URL":"https:\/\/doi.org\/10.3390\/cells10102503","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-691419\/v1","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,22]]}}}