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Covalent targeted radioligands potentiate radionuclide therapy

Nature volume 630, pages 206–213 (2024)Cite this article

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Abstract

Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer1,2,3,4. A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge5,6. A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the ‘click’ SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted β- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets.

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Fig. 1: Development of a CTR by SuFEx engineering and successful proof of concept in tumour-bearing mice.
Fig. 2: CTR-FAPIs irreversibly bind to FAP through covalent ligation to the tyrosine residues, leading to higher uptake and longer retention in cancer cells.
Fig. 3: CTR-FAPIs improve tumour uptake in tumour-bearing mice and precisely detect lesions in patients with cancer.
Fig. 4: SuFEx-engineered FAPI improves the retention of radionuclides in tumours and causes almost-complete tumour regression.
Fig. 5: Performance of SuFEx-engineered FAPI in targeted-α-therapy in an HT-1080-FAP cell-line-derived xenograft model and an SDC-PDX model.

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Data availability

The structural coordinates of proteins for analysis are available in the PDB with accession codes 1L5G, 7T11, 1Z68 and 5O5T. All other data supporting the findings of this study are included in the Article and its Supplementary Information. Source data are provided with this paper.

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Acknowledgements

We thank C. Wang, X. Wang, W. Zhou and X. Liu for experimental assistance with tandem mass analysis; S. Huang and L. Ma for assistance with autoradioluminography; Q. Wang for experimental assistance with SPR; C. Pan for assistance with computational studies; and L. Lai for suggestions on the manuscript. The high-resolution mass-spectrometry and confocal-imaging measurements were performed at the Analytical Instrumentation Center of Peking University. This study was funded by the National Natural Science Foundation of China (NSFC, grant 22225603), the Ministry of Science and Technology of the People’s Republic of China (grant 2021YFA1601400), the Beijing Municipal Natural Science Foundation (grant Z200018) to Z. Liu, the Program of the Local Science and Technology Development (Gansu province, grant YDZX20216200001201) to X.-Y.C., Peking University Clinical Scientist Training Program (grant BMU2024PYJH006) to Z. Li, the NSFC grant 32301152 and the Beijing Natural Science Foundation (grant 7232351) to Z.K., the NSFC grant 82071967 to L.H., the Capital’s Funds for Health Improvement and Research (grant 2022-2Z-2154) to Z.Y.

Author information

Author notes

  1. These authors contributed equally: Xi-Yang Cui, Zhu Li, Ziren Kong

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, P. R. China

    Xi-Yang Cui, Yu Liu, Zihao Wen, Changlun Wang, Junyi Chen, Mengxin Xu, Yiyan Li, Jingyue Gao & Zhibo Liu

  2. Changping Laboratory, Beijing, P. R. China

    Xi-Yang Cui, Hao Meng, Mengxin Xu & Zhibo Liu

  3. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, P. R. China

    Zhu Li, Zhi Yang & Zhibo Liu

  4. Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China

    Ziren Kong & Shaoyan Liu

  5. Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine and State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China

    Wenjia Zhu, Zhixin Hao & Li Huo

  6. Peking University–Tsinghua University Center for Life Sciences, Peking University, Beijing, P. R. China

    Zhibo Liu

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Contributions

Z. Liu conceived the study. Z. Liu and X.-Y.C. performed the molecular design. X.-Y.C., assisted by Y. Liu, Z.W., C.W. and J.G., performed the chemical analysis, characterization and in vitro studies. Z. Li and Z.K. performed the clinical study. X.-Y.C., assisted by Y. Liu, Z.W. and M.X., performed the radiolabelling, PET imaging and therapy studies. H.M., Y. Li and X.-Y.C. performed the theoretical calculation. J.C. produced 86Y and assisted X.-Y.C. with the dosimetry. S.L., Z.Y., L.H., W.Z. and Z.H. provided suggestions for the clinical study. X.-Y.C., Z. Liu, Z.K. and Z. Li analysed the data. Z. Liu and X.-Y.C. wrote the manuscript with input from all authors. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Zhibo Liu.

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Competing interests

Z. Liu and X.-Y.C. are co-inventors on a relevant patent application (PCT/CN2023/096111) filed by Peking University, and a relevant provisional patent application (PCT/CN2023/096106) filed by Changping Laboratory. Z. Liu is a co-founder of and scientific advisor for BoomRay Pharmaceuticals. The remaining authors declare no competing interests.

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Extended data figures and tables

Extended Data Fig. 1 Synthetic routes for the CTR-FAPI vectors and their radiolabelling.

a, Synthetic route or FAP-targeting CTRs in this work. b, Chemical structure of the radiolabelled CTR-FAPIs. The grey lines show the minimum and maximum distance between the modification starting carbon and the sulfur (VI) calculated by MOE. c, Quantitative comparison of the stability of 177Lu-labelled CTR-FAPIs by radio-HPLC. n = 3, mean ± s.d. is depicted, one-way ANOVA followed by Tukey’s multiple comparison test. d, Condition and results of 68Ga-labelling. e, Condition and results of 177Lu-labelling. See SI for 86Y and 225Ac radiolabelling details.

Source Data

Extended Data Fig. 2 Chemical structures, target affinity and stability profile of CTR-FAPIs and related molecules.

a, Chemical structures of the CTR-FAPI vectors and fluorescent probes discussed in this work. b, IC50 values obtained by in-cell competitive binding assay with [68Ga]Ga-FAPI-04. Every test was performed at least twice individually. c, Representative IC50 curves of FAPI-04, FAPI-pFS and FAPI-mFS competing with [68Ga]Ga-FAPI-04 to bind HT-1080-FAP cells (n = 4). d, Representative IC50 curves of FAPI-04, FAPI-pFS and FAPI-mFS tested in enzyme activity inhibition assays to evaluate the FAP binding selectivity (n = 4). e, Evaluation of the stability of FAPI-SF, FAPI-pFS and FAPI-mFS vectors under common 68Ga-labelling condition or physiological condition by UPLC. Data are mean ± s.d. (c,d).

Source Data

Extended Data Fig. 3 Further study of the covalent binding mechanism.

a, Proposed kinetic process of CTR-FAPIs binding to FAP based on experimental results and literature evidence. b, Control experiment suggesting FAPI-04 forms a reversible acid-sensitive covalent bond with FAP, while CTR-FAPIs, e.g., FAPI-mFS (3), forms an irreversible covalent bond. c, Key kinetic constants obtained by theoretical derivation are concluded. d,e, Investigation of the irreversible binding rate (kinact) between [177Lu]Lu-FAPI-mFS and FAP by autoradioluminography-based kinetic study (d). Data are mean ± s.d. (e). Lane splits are shown by yellow boxes. cInt B, the concentration of Int B at the moment. f, Y122 at Integrin αvβ3 (PDB: 1L5G) (above). The cyan spheres are Mn2+. Y205 at SSTR2 (PDB: 7T11) (below); proteins are in grey; ligands are in blue and the selected potential residues for covalent binding are in red. Data are representative of two (b) or three (d) independent experiments.

Source Data

Extended Data Fig. 4 Additional pharmacological insights on CTR-FAPIs.

a–c, Surface plasmon resonance (SPR) analysis of FAPI-04 (black), FAPI-pFS (blue), FAPI-mFS (red) and FAPI-mHS (green) binding to FAP, respectively. a, SPR sensorgrams of the single-cycle kinetics. The arrows refer to the subsequent injections in the association phase. RU, resonance units. b, Plot of the association rate (x-axis) and dissociation rate (y-axis) based on SPR. c, Summary of kinetic constants according to SPR assay. d, Representative confocal fluorescence images of visualizing the cellular efflux of FAPI-mFS-AF488 probe (6) and its FS-hydrolysed control (7). The HT-1080-FAP cells were pre-treated with fluorescent probes 6 or 7 (10 μM in MEM medium) for 2 h, followed by incubation with probe-free medium for 1–72 h; scale bar = 25 μm. e, Representative confocal fluorescence images showing the localization of probe 6 in cell; DAPI = 4’,6-diamidino-2-phenylindole, for DNA staining; scale bar = 5 μm. f, Fluorescence intensity analysis in HT-1080-FAP cells according to the examined field of view by confocal microscopy (n = 3 fields). Mean ± s.d. is depicted. Data at 72 h are analysed by two-tailed unpaired Student’s t-test. g, Schematic relationship between pharmacokinetics, binding kinetics and radio-pharmacodynamics for radiopharmaceuticals in the dynamic blood flow scenario. Data are representative of two independent experiments. The illustrations in g were created with BioRender.

Source Data

Extended Data Fig. 5 Binding selectivity and metabolic stability of CTR-FAPIs.

a, IC50 summary of FAPI-04, FAPI-pFS or FAPI-mFS inhibiting FAP, DPP-4 or PREP based on fluorescent assay, respectively; SI, selectivity index (calculated as [IC50 (PREP)/IC50 (FAP)]). b, Autoradioluminographic analysis of the covalent binding of CTR-FAPIs with human serum proteins in vitro. The ligation ratios in per cent are presented beyond corresponding bands. c, Autoradioluminographic analysis of the covalent binding of [177Lu]Lu-CTR-FAPIs with plasma proteins in mice. d, Co-location of the autoradioluminography and Coomassie blue staining results of the human serum incubating with [177Lu]Lu-FAPI-mFS up to 12 h. e, Renal metabolic stability of [177Lu]Lu-FAPI-mFS in NU/NU mouse by radio-HPLC analysis. Top, the 254 nm UV absorption spectra of natLu-FAPI-mFS, whose m/z was determined in HPLC–mass spectrometry. Middle, the radio-HPLC spectra of [177Lu]Lu-FAPI-mFS before injection. Bottom, the radio-HPLC spectra of urine sample 30 min post-injection of [177Lu]Lu-FAPI-mFS. f, Radio-HPLC spectra of [68Ga]Ga-FAPI-mFS before and after renal metabolism within PET/CT period. g, PET/CT images showed for the lesions which [68Ga]Ga-FAPI-04 identified, but [68Ga]Ga-FAPI-mFS achieved higher tumour uptake. h, The reduction in SUVmax of key organs in patient 1 four hours after injection. Data are representative of two (b–d) independent experiments.

Source Data

Extended Data Fig. 6 Further therapeutic data for 177Lu- or 225Ac-labelled CTR-FAPIs.

a–c, NU/NU mice were implanted subcutaneously with HT-1080-FAP cells, followed by intravenous injection of saline, [177Lu]Lu-FAPI-04, [177Lu]Lu-FAPI-mFS. n = 7 mice for each group of [177Lu]Lu-FAPI-mFS, n = 8 mice for saline and [177Lu]Lu-FAPI-04. a, Maximum tumour response waterfall plot till Day 30. b, Tumour volume curve of an individual mouse. c, Photographs of representative tumours at day 14 in a repeated trial. d–g, NU/NU mice were implanted subcutaneously with HT-1080-FAP cells, followed by intravenous injection of saline, [225Ac]Ac-FAPI-04 or [225Ac]Ac-FAPI-mFS. d, Treatment scheme. n = 6 mice for each group of [225Ac]Ac-FAPI-mFS 22.2 kBq, n = 7 mice for saline, [225Ac]Ac-FAPI-04 and [225Ac]Ac-FAPI-mFS 33.3 kBq. e, Tumour volume curves of the group. f, Maximum tumour response waterfall plot. g, Tumour volume curves of an individual mouse. Two-tailed unpaired Student’s t-test was applied (e on day ~15). h, Selected results from complete blood count (CBC) and blood biochemistry tests. ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ALB = Albumin; UREA = Urea in serum; CREA = Serum creatinine. n = 3, data shown are mean ± s.d (e,h). One-way ANOVA followed by Tukey’s multiple comparison test was applied.

Source Data

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Cui, XY., Li, Z., Kong, Z. et al. Covalent targeted radioligands potentiate radionuclide therapy. Nature 630, 206–213 (2024). https://doi.org/10.1038/s41586-024-07461-6

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