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An antibody-radionuclide conjugate targets fibroblast activation protein for cancer therapy

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

Abstract

Purpose

Fibroblast activation protein is one of the most attractive targets for tumor diagnosis and therapy. There have been many successful clinical translations with small molecules and peptides, yet only a few anti-FAP antibody diagnostic or therapeutic agents have been reported. Antibodies often feature good tumor selectivity and long tumor retention, which may be a better-match with therapeutic radionuclides (e.g.,177Lu, 225Ac) for cancer therapy. Here we report a 177Lu-labeled anti-FAP antibody, PKU525, as a therapeutic radiopharmaceutical for FAP-targeted radiotherapy.

Methods

The anti-FAP antibody is produced as a derivative of sibrotuzumab. The pharmacokinetics and blocking study are performed with 89Zr-labeled antibody by PET imaging. The conjugation strategies have been screened and tested with SPECT imaging through 177Lu-labeling. The biodistribution and radiotherapy studies are performed on 177Lu-labeled anti-FAP antibody in NU/NU mice-bearing HT-1080-FAP tumors.

Results

A multiple time-point PET imaging study shows that the tumor accumulation of [89Zr]Zr-DFO-PKU525 is intense, selective, and relatively rapid. The time activity curve indicates that the tumor uptake continually increases until reaches the highest uptake (SUVmax = 18.4 ± 2.3, n = 4) at 192 h, then gradually declines. Radioactivity rapidly cleared from the blood, liver, and other major organs, resulting in high tumor-to-background ratios. An in vivo blocking experiment suggests that [89Zr]Zr-DFO-PKU525 is FAP-specific and the uptake in FAP-negative tumors is almost negligible. Ex vivo biodistribution study shows that the tumor uptake of [177Lu]Lu-DOTA-NCS-PKU525 is 23.04 ± 5.11% ID/g, 33.2 ± 6.36% ID/g, 19.87 ± 6.84% ID/g and 19.02 ± 5.90% ID/g at 24 h, 96 h, 168 h, and 240 h after injection (n = 5), which is corroborated with the PET imaging. In therapeutic assays, multiple doses of [177Lu]Lu-DOTA-NCS-PKU525 have been tested in tumor-bearing mice, and the data suggests that 3.7 MBq may be sufficient to completely suppress the tumor growth in mice without showing observable side effects.

Conclusion

A FAP-targeted antibody-radionuclide conjugate was developed and evaluated in vitro and in vivo. Its tumor accumulation is rapid and high with a clean background. It remarkably suppresses the tumors in mice while the side effect is almost negligible, showing that it is promising for further clinical translational studies.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the facility support from the Analytical Instrumentation Center of Peking University.

Funding

This study was funded by the Beijing Municipal Natural Science Foundation (Grant No. Z200018), the National Natural Science Foundation of China (Grant No. 22225603), the Ministry of Science and Technology of the People’s Republic of China (Grant Nos. 2021YFA1601400), and Changping Laboratory under the project number (2022C-07-01), the Central Guidance for Local Science and Technology Development Projects (No. 202138-03) to Z.L.

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Author notes

  1. Mengxin Xu and Junyi Chen contributed equally to this work

Authors and Affiliations

  1. Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China

    Mengxin Xu, Junyi Chen, Pu Zhang & Zhibo Liu

  2. Boomray Pharmaceuticals (Beijing) Co., Ltd., Beijing, China

    Jie Cai

  3. Changping Laboratory, Beijing, 102206, China

    Hanbo Song & Zhibo Liu

  4. Department of Nuclear Medicine, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, Beijing, 100142, China

    Zhu Li & Zhibo Liu

  5. Peking University-Tsinghua University Center for Life Sciences, Beijing, 100871, China

    Zhibo Liu

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  1. Mengxin Xu
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Pu Zhang, Mengxin Xu, Junyi Chen, and Zhibo Liu are the consultants of Boomray Pharmaceuticals (Beijing) Co., Ltd.

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Xu, M., Chen, J., Zhang, P. et al. An antibody-radionuclide conjugate targets fibroblast activation protein for cancer therapy. Eur J Nucl Med Mol Imaging 50, 3214–3224 (2023). https://doi.org/10.1007/s00259-023-06300-6

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