Preclinical evaluation of podoplanin-targeted alpha-radioimmunotherapy with the novel antibody nz-16 for malignant mesothelioma

Hitomi Sudo; Atsushi B. Tsuji; Aya Sugyo; Mika K. Kaneko; Yukinari Kato; Kotaro Nagatsu; Hisashi Suzuki; Tatsuya Higashi

doi:10.3390/cells10102503

Preclinical evaluation of podoplanin-targeted alpha-radioimmunotherapy with the novel antibody nz-16 for malignant mesothelioma

Hitomi Sudo, Atsushi B. Tsuji, Aya Sugyo, Mika K. Kaneko, Yukinari Kato, Kotaro Nagatsu, Hisashi Suzuki, Tatsuya Higashi

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Abstract

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 com-petitive inhibition assays using PDPN-expressing H226 mesothelioma cells. The biodistribution of¹¹¹ In-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 with⁹⁰ Y-and²²⁵ Ac-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 with²²⁵ Ac-and⁹⁰ Y-labeled NZ-16 had a significantly higher antitumor effect than RIT with⁹⁰ Y-labeled NZ-12.²²⁵ Ac-labeled NZ-16 induced a larger amount of necrotic change and showed a tendency to suppress tumor volumes and prolonged survival than⁹⁰ Y-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.

Original language	English
Article number	2503
Journal	Cells
Volume	10
Issue number	10
DOIs	https://doi.org/10.3390/cells10102503
Publication status	Published - 2021 Oct

Keywords

Actinium-225
Improved efficacy
Molecular radiotherapy
Prolonged survival
Tumor volume reduction

ASJC Scopus subject areas

Medicine(all)

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10.3390/cells10102503

Cite this

@article{d9d7d4ae0e054911bbc0913edba15c5c,

title = "Preclinical evaluation of podoplanin-targeted alpha-radioimmunotherapy with the novel antibody nz-16 for malignant mesothelioma",

abstract = "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 com-petitive inhibition assays using PDPN-expressing H226 mesothelioma cells. The biodistribution of111 In-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 with90 Y-and225 Ac-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 with225 Ac-and90 Y-labeled NZ-16 had a significantly higher antitumor effect than RIT with90 Y-labeled NZ-12.225 Ac-labeled NZ-16 induced a larger amount of necrotic change and showed a tendency to suppress tumor volumes and prolonged survival than90 Y-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.",

keywords = "Actinium-225, Improved efficacy, Molecular radiotherapy, Prolonged survival, Tumor volume reduction",

author = "Hitomi Sudo and Tsuji, {Atsushi B.} and Aya Sugyo and Kaneko, {Mika K.} and Yukinari Kato and Kotaro Nagatsu and Hisashi Suzuki and Tatsuya Higashi",

note = "Funding Information: Funding: This work was supported in part by KAKENHI 18K07778 (H.S.), 21K07688 (H.S.), 21K07230 (A.S.), 18H02774 (A.B.T.), 21K07168 (M.K.K.), and 19K07705 (Y.K.), and in part by the Japan Agency for Medical Research and Development (AMED) under Grant Numbers JP21am0401013 (Y.K.) and JP21am0101078 (Y.K.), and 21ym0126002 (T.H.). Funding Information: This work was supported in part by KAKENHI 18K07778 (H.S.), 21K07688 (H.S.), 21K07230 (A.S.), 18H02774 (A.B.T.), 21K07168 (M.K.K.), and 19K07705 (Y.K.), and in part by the Japan Agency for Medical Research and Development (AMED) under Grant Numbers JP21am0401013 (Y.K.) and JP21am0101078 (Y.K.), and 21ym0126002 (T.H.). We thank Yuriko Ogawa, Naoko Kuroda, and Akihito Abe for technical assistance and the staff in the Laboratory Animal Sciences section for animal management. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = oct,

doi = "10.3390/cells10102503",

language = "English",

volume = "10",

journal = "Cells",

issn = "2073-4409",

publisher = "MDPI Multidisciplinary Digital Publishing Institute",

number = "10",

}

TY - JOUR

T1 - Preclinical evaluation of podoplanin-targeted alpha-radioimmunotherapy with the novel antibody nz-16 for malignant mesothelioma

AU - Sudo, Hitomi

AU - Tsuji, Atsushi B.

AU - Sugyo, Aya

AU - Kaneko, Mika K.

AU - Kato, Yukinari

AU - Nagatsu, Kotaro

AU - Suzuki, Hisashi

AU - Higashi, Tatsuya

N1 - Funding Information: Funding: This work was supported in part by KAKENHI 18K07778 (H.S.), 21K07688 (H.S.), 21K07230 (A.S.), 18H02774 (A.B.T.), 21K07168 (M.K.K.), and 19K07705 (Y.K.), and in part by the Japan Agency for Medical Research and Development (AMED) under Grant Numbers JP21am0401013 (Y.K.) and JP21am0101078 (Y.K.), and 21ym0126002 (T.H.). Funding Information: This work was supported in part by KAKENHI 18K07778 (H.S.), 21K07688 (H.S.), 21K07230 (A.S.), 18H02774 (A.B.T.), 21K07168 (M.K.K.), and 19K07705 (Y.K.), and in part by the Japan Agency for Medical Research and Development (AMED) under Grant Numbers JP21am0401013 (Y.K.) and JP21am0101078 (Y.K.), and 21ym0126002 (T.H.). We thank Yuriko Ogawa, Naoko Kuroda, and Akihito Abe for technical assistance and the staff in the Laboratory Animal Sciences section for animal management. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/10

Y1 - 2021/10

N2 - 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 com-petitive inhibition assays using PDPN-expressing H226 mesothelioma cells. The biodistribution of111 In-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 with90 Y-and225 Ac-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 with225 Ac-and90 Y-labeled NZ-16 had a significantly higher antitumor effect than RIT with90 Y-labeled NZ-12.225 Ac-labeled NZ-16 induced a larger amount of necrotic change and showed a tendency to suppress tumor volumes and prolonged survival than90 Y-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.

AB - 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 com-petitive inhibition assays using PDPN-expressing H226 mesothelioma cells. The biodistribution of111 In-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 with90 Y-and225 Ac-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 with225 Ac-and90 Y-labeled NZ-16 had a significantly higher antitumor effect than RIT with90 Y-labeled NZ-12.225 Ac-labeled NZ-16 induced a larger amount of necrotic change and showed a tendency to suppress tumor volumes and prolonged survival than90 Y-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.

KW - Actinium-225

KW - Improved efficacy

KW - Molecular radiotherapy

KW - Prolonged survival

KW - Tumor volume reduction

UR - http://www.scopus.com/inward/record.url?scp=85115407890&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85115407890&partnerID=8YFLogxK

U2 - 10.3390/cells10102503

DO - 10.3390/cells10102503

M3 - Article

C2 - 34685483

AN - SCOPUS:85115407890

VL - 10

JO - Cells

JF - Cells

SN - 2073-4409

IS - 10

M1 - 2503

ER -

Preclinical evaluation of podoplanin-targeted alpha-radioimmunotherapy with the novel antibody nz-16 for malignant mesothelioma

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