Theranostics using ⁸⁹Zr/¹⁷⁷Lu-labeled antibody targeting erythropoietin-producing hepatocellular A2 (EphA2)

Watabe, Tadashi; Iwasawa, Takumi; Kimura, Hiroyuki; Shirakami, Yoshifumi; Naka, Sadahiro; Kaneda, Kazuko; Kobayashi, Takanori; Omokawa, Marina; Yagi, Yusuke; Tomiyama, Noriyuki; Kato, Kazunori

doi:https://doi.org/10.1007/s00259-025-07139-9

Theranostics using ⁸⁹Zr/¹⁷⁷Lu-labeled antibody targeting erythropoietin-producing hepatocellular A2 (EphA2)

Watabe, Tadashi; Iwasawa, Takumi; Kimura, Hiroyuki et al.

European Journal of Nuclear Medicine and Molecular Imaging, 2025

Number of Access:1,213（2025-07-05 18:50 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/100453

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Title	Theranostics using ⁸⁹Zr/¹⁷⁷Lu-labeled antibody targeting erythropoietin-producing hepatocellular A2 (EphA2)
Creator	NRID 1000090648932 1000090648932 ORCID 0000-0001-8658-2395 0000-0001-8658-2395 researchmap permalink twosaka2018 twosaka2018 Scopus Author ID 57421862900 57421862900 CreatorName Watabe, Tadashi
	NRID 1000070906297 1000070906297 CreatorName Iwasawa, Takumi
	NRID 1000050437240 1000050437240 CreatorName Kimura, Hiroyuki
	NRID 1000000560400 1000000560400 researchmap permalink e5221 e5221 Scopus Author ID 6603428576 6603428576 CreatorName Shirakami, Yoshifumi
	NRID 1000060599843 1000060599843 researchmap permalink _sada_ _sada_ CreatorName Naka, Sadahiro
	NRID 1000000533209 1000000533209 ORCID 0000-0001-6657-5059 0000-0001-6657-5059 researchmap permalink read0131912 read0131912 CreatorName Kaneda, Kazuko
	CreatorName Kobayashi, Takanori
	CreatorName Omokawa, Marina
	NRID 1000090802207 1000090802207 CreatorName Yagi, Yusuke
	NRID 1000050294070 1000050294070 researchmap permalink 3430 3430 Scopus Author ID 7006024942 7006024942 CreatorName Tomiyama, Noriyuki
	NRID 1000060233780 1000060233780 CreatorName Kato, Kazunori
Subject	Antibody
	EphA2
	Lutetium (177Lu)
	Theranostics
	Zirconium (89Zr)
Description	The version of record of this article, first published in European Journal of Nuclear Medicine and Molecular Imaging, is available online at Publisher’s website: https://doi.org/10.1007/s00259-025-07139-9.
Abstract	Purpose: Erythropoietin-producing hepatocellular A2 (EphA2) is abundantly expressed in various types of cancers. This study aimed to assess the therapeutic effect of ¹⁷⁷Lu-labeled EphA2 antibody in combination with PET imaging using ⁸⁹Zr-labeled antibody. Methods: An EphA2 monoclonal antibody (mAb) (clone 230-1) was labeled with ⁸⁹Zr and ¹⁷⁷Lu using DFO and NOTA chelators, respectively. HT-1080 (EphA2-expressing human fibrosarcoma) xenograft mice were intravenously administered [⁸⁹Zr]Zr-EphA2 mAb (n = 6) for PET scanning, and [¹⁷⁷Lu]Lu-EphA2 mAb (n = 12) to evaluate the biodistribution and specificity of uptake in HT-1080 xenografts in a blocking study. The antitumor effect was evaluated by administering 10 (n = 9) or 3MBq (n = 9) of [¹⁷⁷Lu]Lu-EphA2 mAb, non-radiolabeled EphA2 mAb (n = 6), [¹⁷⁷Lu]LuCl3 solution (10MBq, n = 6), or saline solution (control, n = 4) to HT-1080 xenograft mice. Body weight monitoring and preliminary blood tests were performed to evaluate toxicity. Immunohistochemical staining for EphA2 was performed using HT-1080 xenografts. Results: On [⁸⁹Zr]Zr-EphA2 mAb PET, a markedly high accumulation was observed in the tumor xenograft 1 day after administration (SUVmax, 11.8 ± 4.98), which increased on day 5 (SUVmax, 20.1 ± 6.42). [¹⁷⁷Lu]Lu-EphA2 mAb exhibited excellent uptake and retention in HT-1080 xenografts (49.4 ± 10.8%IA/g at 24 h and 101.8 ± 26.3%IA/g at 72 h after administration). Normal organs did not show high physiological uptake, except for the blood (16.9 ± 0.43%IA/g at 24 h and 16.1 ± 4.9%IA/g at 72 h). The blocking study demonstrated a significant reduction of tumor uptake 24 h after administration (47.2 ± 8.22 vs. 10.7 ± 0.52%IA/g, P = 0.02). Substantial tumor growth inhibition, and complete remission without severe toxicity (6 of 18 mice), was observed in HT-1080 xenograft mice after [¹⁷⁷Lu]Lu-EphA2 mAb (3 and 10 MBq) administration. The non-radiolabeled EphA2 mAb showed a minor treatment effect compared with [¹⁷⁷Lu]Lu-EphA2 mAb. Immunohistochemical staining revealed high EphA2 expression in the HT-1080 xenografts. Conclusion: [⁸⁹Zr]Zr-/[¹⁷⁷Lu]Lu-EphA2 mAb demonstrated high retention in tumors, and [¹⁷⁷Lu]Lu-EphA2 mAb exhibited marked tumor shrinkage. EphA2 is a promising theranostics target for potential application in various types of cancer.
Publisher	Springer
Source Title	European Journal of Nuclear Medicine and Molecular Imaging
Date of Issued	2025-02-12
Language	English
Handle URL	https://hdl.handle.net/11094/100453
PISSN	16197070
eISSN	16197089
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1007/s00259-025-07139-9
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	European Journal of Nuclear Medicine and Molecular Imaging. 2025
DC.title	Theranostics using ⁸⁹Zr/¹⁷⁷Lu-labeled antibody targeting erythropoietin-producing hepatocellular A2 (EphA2)
DC.creator	Watabe, Tadashi
	Iwasawa, Takumi
	Kimura, Hiroyuki
	Shirakami, Yoshifumi
	Naka, Sadahiro
	Kaneda, Kazuko
	Kobayashi, Takanori
	Omokawa, Marina
	Yagi, Yusuke
	Tomiyama, Noriyuki
	Kato, Kazunori
DC.publisher	Springer
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-02-12
DC.identifier	https://doi.org/10.1007/s00259-025-07139-9
DC.subject	Antibody
	EphA2
	Lutetium (177Lu)
	Theranostics
	Zirconium (89Zr)
DC.description	The version of record of this article, first published in European Journal of Nuclear Medicine and Molecular Imaging, is available online at Publisher’s website: https://doi.org/10.1007/s00259-025-07139-9.
DCTERMS.abstract	Purpose: Erythropoietin-producing hepatocellular A2 (EphA2) is abundantly expressed in various types of cancers. This study aimed to assess the therapeutic effect of ¹⁷⁷Lu-labeled EphA2 antibody in combination with PET imaging using ⁸⁹Zr-labeled antibody. Methods: An EphA2 monoclonal antibody (mAb) (clone 230-1) was labeled with ⁸⁹Zr and ¹⁷⁷Lu using DFO and NOTA chelators, respectively. HT-1080 (EphA2-expressing human fibrosarcoma) xenograft mice were intravenously administered [⁸⁹Zr]Zr-EphA2 mAb (n = 6) for PET scanning, and [¹⁷⁷Lu]Lu-EphA2 mAb (n = 12) to evaluate the biodistribution and specificity of uptake in HT-1080 xenografts in a blocking study. The antitumor effect was evaluated by administering 10 (n = 9) or 3MBq (n = 9) of [¹⁷⁷Lu]Lu-EphA2 mAb, non-radiolabeled EphA2 mAb (n = 6), [¹⁷⁷Lu]LuCl3 solution (10MBq, n = 6), or saline solution (control, n = 4) to HT-1080 xenograft mice. Body weight monitoring and preliminary blood tests were performed to evaluate toxicity. Immunohistochemical staining for EphA2 was performed using HT-1080 xenografts. Results: On [⁸⁹Zr]Zr-EphA2 mAb PET, a markedly high accumulation was observed in the tumor xenograft 1 day after administration (SUVmax, 11.8 ± 4.98), which increased on day 5 (SUVmax, 20.1 ± 6.42). [¹⁷⁷Lu]Lu-EphA2 mAb exhibited excellent uptake and retention in HT-1080 xenografts (49.4 ± 10.8%IA/g at 24 h and 101.8 ± 26.3%IA/g at 72 h after administration). Normal organs did not show high physiological uptake, except for the blood (16.9 ± 0.43%IA/g at 24 h and 16.1 ± 4.9%IA/g at 72 h). The blocking study demonstrated a significant reduction of tumor uptake 24 h after administration (47.2 ± 8.22 vs. 10.7 ± 0.52%IA/g, P = 0.02). Substantial tumor growth inhibition, and complete remission without severe toxicity (6 of 18 mice), was observed in HT-1080 xenograft mice after [¹⁷⁷Lu]Lu-EphA2 mAb (3 and 10 MBq) administration. The non-radiolabeled EphA2 mAb showed a minor treatment effect compared with [¹⁷⁷Lu]Lu-EphA2 mAb. Immunohistochemical staining revealed high EphA2 expression in the HT-1080 xenografts. Conclusion: [⁸⁹Zr]Zr-/[¹⁷⁷Lu]Lu-EphA2 mAb demonstrated high retention in tumors, and [¹⁷⁷Lu]Lu-EphA2 mAb exhibited marked tumor shrinkage. EphA2 is a promising theranostics target for potential application in various types of cancer.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	100453
citation_title	Theranostics using ⁸⁹Zr/¹⁷⁷Lu-labeled antibody targeting erythropoietin-producing hepatocellular A2 (EphA2)
citation_author	Watabe, Tadashi
	Iwasawa, Takumi
	Kimura, Hiroyuki
	Shirakami, Yoshifumi
	Naka, Sadahiro
	Kaneda, Kazuko
	Kobayashi, Takanori
	Omokawa, Marina
	Yagi, Yusuke
	Tomiyama, Noriyuki
	Kato, Kazunori
citation_publisher	Springer
citation_language	English
citation_date	2025-02-12
citation_journal_title	European Journal of Nuclear Medicine and Molecular Imaging
citation_doi	https://doi.org/10.1007/s00259-025-07139-9
citation_public_url	https://hdl.handle.net/11094/100453

Theranostics using ⁸⁹Zr/¹⁷⁷Lu-labeled antibody targeting erythropoietin-producing hepatocellular A2 (EphA2)

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