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Purpose <p>Erythropoietin-producing hepatocellular A2 (EphA2) is abundantly expressed in various types of cancers. This study aimed to assess the therapeutic effect of <sup>177</sup>Lu-labeled EphA2 antibody in combination with PET imaging using <sup>89</sup>Zr-labeled antibody.</p> Methods <p>An EphA2 monoclonal antibody (mAb) (clone 230-1) was labeled with <sup>89</sup>Zr and <sup>177</sup>Lu using DFO and NOTA chelators, respectively. HT-1080 (EphA2-expressing human fibrosarcoma) xenograft mice were intravenously administered [<sup>89</sup>Zr]Zr-EphA2 mAb (<i>n</i> = 6) for PET scanning, and [<sup>177</sup>Lu]Lu-EphA2 mAb (<i>n</i> = 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 (<i>n</i> = 9) or 3MBq (<i>n</i> = 9) of [<sup>177</sup>Lu]Lu-EphA2 mAb, non-radiolabeled EphA2 mAb (<i>n</i> = 6), [<sup>177</sup>Lu]LuCl<sub>3</sub> solution (10MBq, <i>n</i> = 6), or saline solution (control, <i>n</i> = 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.</p> Results <p>On [<sup>89</sup>Zr]Zr-EphA2 mAb PET, a markedly high accumulation was observed in the tumor xenograft 1&#xa0;day after administration (SUVmax, 11.8 ± 4.98), which increased on day 5 (SUVmax, 20.1 ± 6.42). [<sup>177</sup>Lu]Lu-EphA2 mAb exhibited excellent uptake and retention in HT-1080 xenografts (49.4 ± 10.8%IA/g at 24&#xa0;h and 101.8 ± 26.3%IA/g at 72&#xa0;h after administration). Normal organs did not show high physiological uptake, except for the blood (16.9 ± 0.43%IA/g at 24&#xa0;h and 16.1 ± 4.9%IA/g at 72&#xa0;h). The blocking study demonstrated a significant reduction of tumor uptake 24&#xa0;h after administration (47.2 ± 8.22 vs. 10.7 ± 0.52%IA/g, <i>P</i> = 0.02). Substantial tumor growth inhibition, and complete remission without severe toxicity (6 of 18 mice), was observed in HT-1080 xenograft mice after [<sup>177</sup>Lu]Lu-EphA2 mAb (3 and 10 MBq) administration. The non-radiolabeled EphA2 mAb showed a minor treatment effect compared with [<sup>177</sup>Lu]Lu-EphA2 mAb. Immunohistochemical staining revealed high EphA2 expression in the HT-1080 xenografts.</p> Conclusion <p>[<sup>89</sup>Zr]Zr-/[<sup>177</sup>Lu]Lu-EphA2 mAb demonstrated high retention in tumors, and [<sup>177</sup>Lu]Lu-EphA2 mAb exhibited marked tumor shrinkage. EphA2 is a promising theranostics target for potential application in various types of cancer.</p>

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

  • 期刊论文

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  • 发表日期：

    2025年2月12日

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

摘要

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.