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Therapeutic efficacy of an alpha-particle emitter labeled anti-GD2 humanized antibody against osteosarcoma—a proof of concept study

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Current treatments for osteosarcoma (OS) have a poor prognosis, particularly for patients with metastasis and recurrence, underscoring an urgent need for new targeted therapies to improve survival. Targeted alpha-particle therapy selectively delivers cytotoxic payloads to tumors with radiolabeled molecules that recognize tumor-associated antigens. We have recently demonstrated the potential of an FDA approved, humanized anti-GD2 antibody, hu3F8, as a targeted delivery vector for radiopharmaceutical imaging of OS. The current study aims to advance this system for alpha-particle therapy of OS.

Methods

The hu3F8 antibody was radiolabeled with actinium-225, and the safety and therapeutic efficacy of the [225Ac]Ac-DOTA-hu3F8 were evaluated in both orthotopic murine xenografts of OS and spontaneously occurring OS in canines.

Results

Significant antitumor activity was proven in both cases, leading to improved overall survival. In the murine xenograft’s case, tumor growth was delayed by 16–18 days compared to the untreated cohort as demonstrated by bioluminescence imaging. The results were further validated with magnetic resonance imaging at 33 days after treatment, and microcomputed tomography and planar microradiography post-mortem. Histological evaluations revealed radiation-induced renal toxicity, manifested as epithelial cell karyomegaly and suggestive polyploidy in the kidneys, suggesting rapid recovery of renal function after radiation damage. Treatment of the two canine patients delayed the progression of metastatic spread, with an overall survival time of 211 and 437 days and survival beyond documented metastasis of 111 and 84 days, respectively.

Conclusion

This study highlights the potential of hu3F8-based alpha-particle therapy as a promising treatment strategy for OS.

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Data availability

Datasets generated/analyzed in the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The hu3F8 antibody was provided by N-K Cheung (Memorial Sloan-Kettering Cancer Center, New York, NY, USA). Actinium-225 is in short supply, in part due to the tremendous clinical interest in this alpha-emitting radionuclide. The authors thank the Department of Energy, Isotope Program for making this radionuclide available to us at cost for our studies. Cheri Rice assisted with the canine studies.

Funding

This work was supported by the National Institutes Health grants: R01 CA116477, R01 CA187037, and R01 CA239124.

Author information

Author notes

  1. Ioanna Liatsou and Yingli Fu contributed equally to this work, as first authors.

Authors and Affiliations

  1. Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ioanna Liatsou, Yingli Fu, Zhi Li, Mahmud Hasan, Jing Yu, Joseph Piccolo, Allison Cartee, Yong Du, Dara L. Kraitchman & George Sgouros

  2. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Xin Guo & Kathleen Gabrielson

  3. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Hao Wang

  4. Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, USA

    Jeffrey Bryan

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  1. Ioanna Liatsou
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  2. Yingli Fu
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Contributions

IL and YF designed and performed all the murine experiments (including radiolabeling the Ab), collected, and analyzed the data.

IL wrote the original draft of the manuscript.

ZL, MH, JP, and AC assisted in the murine experiments.

JY assisted with the radiolabeling experiments.

XG and KG performed the intratibial inoculations for the canine OS xenograft mouse model development.

HW helped and reviewed the statistical analysis of the data.

YD analyzed canine biodistribution images and provided input data for the red marrow dosimetry estimates.

JB contributed to the interpretation of canine therapy outcome and also the initial characterization of the 3F8 reactivity against GD2.

KG assisted/guided the histopathological evaluation of the H&E sections.

DLK performed treatment of the canine patients.

DLK and GS acquired funding and supervised in the design and interpretation of the experiments.

All authors reviewed and edited the manuscript.

Corresponding author

Correspondence to Ioanna Liatsou.

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Ethics approval

Animal protocols were approved by the Animal Care and Use Committee of the Johns Hopkins University School of Medicine. Client-owned dogs with confirmed metastatic OS were recruited from owners with written informed consent.

Competing interests

The authors declare no competing interests.

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Liatsou, I., Fu, Y., Li, Z. et al. Therapeutic efficacy of an alpha-particle emitter labeled anti-GD2 humanized antibody against osteosarcoma—a proof of concept study. Eur J Nucl Med Mol Imaging 51, 1409–1420 (2024). https://doi.org/10.1007/s00259-023-06528-2

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  • DOI: https://doi.org/10.1007/s00259-023-06528-2

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