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Theranostic application of 64Cu/177Lu-labeled anti-Trop2 monoclonal antibody in pancreatic cancer tumor models

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Abstract

Purpose

Pancreatic cancer is a malignant tumor with a high degree of malignancy, strong heterogeneity, and high lethality. Trop2 is a transmembrane glycoprotein associated with the occurrence, development, and poor prognosis of pancreatic cancer. This study aims to develop 64Cu/177Lu-labeled anti-Trop2 monoclonal antibody (hIMB1636) for positron emission tomography (PET) imaging and radioimmunotherapy (RIT) application in pancreatic cancer tumor models.

Methods

The binding kinetics of hIMB1636 to Trop2 antigen was measured by Biolayer interferometry (BLI). Western blotting was used to screen the Trop2 expression of pancreatic cancer cell lines. Flow cytometry and cell immunofluorescence were used to evaluate the binding ability of hIMB1636 and Trop2 on the cell surface. hIMB1636 were conjugated with p-SCN-Bn-NOTA (NOTA) and DOTA-NHS-ester (DOTA) for 64Cu and 177Lu radiolabeling respectively. ImmunoPET imaging and RIT studies were performed using 64Cu-NOTA-hIMB1636 and 177Lu-DOTA-hIMB1636 in subcutaneous pancreatic cancer tumor models.

Results

hIMB1636 had a strong binding affinity to Trop2 according to the results of BLI. The T3M-4 cell line showed the strongest expression of Trop2 and specific binding ability of hIMB1636 according to the results of Western blotting, flow cytometry, and cell immunofluorescence. The radiochemical purity of 64Cu-NOTA-hIMB1636 and 177Lu-DOTA-hIMB1636 exceeded 95%. PET imaging showed gradually an accumulation of 64Cu-NOTA-hIMB1636 in T3M-4 tumor models. The maximum tumor uptake was 8.95 ± 1.07%ID/g (n = 4) at 48 h post injection (p.i.), which had significant differences with T3M-4-blocked and PaTu8988-negative groups (P < 0.001). The high-177Lu-hIMB1636 group demonstrated the strongest tumor suppression with standardized tumor volume about 94.24 ± 14.62% (n = 5) at 14 days p.i., significantly smaller than other groups (P < 0.05). Ex vivo biodistribution and histological staining verified the in vivo PET imaging and RIT results.

Conclusions

This study demonstrated that 64Cu/177Lu-labeled hIMB1636 could noninvasively evaluate the expression level of Trop2 and inhibit the Trop2-overexpressed tumor growth in pancreatic cancer tumor models. Further clinical evaluation and translation of Trop2-targeted drug may be of great help in the stratification and management of pancreatic cancer patients.

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  • 15 September 2022

    The article was modified to change the order of the corresponding authors in the corresponding authors field.

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Funding

This work was supported by the Natural Science Foundation of Beijing Municipality (Grant numbers 7224365 and 7202133), the National Natural Science Foundation of China (Grant numbers 82171970, 81871385, 81971642, 82104052, and 82001860), the Beijing Science Foundation for Distinguished Young Scholars (Grant number JQ21025), the Peking University Medicine Fund of Fostering Young Scholars’ Scientific & Technological Innovation (Grant number BMU2022PY006), the Clinical Medicine Plus X-Youth Scholars Project of Peking University (Grant number PKU2020LCXQ023), the CAMS Innovation Fund for Medical Sciences (CIFMS, Grant number 2021-I2M-1-026), and the Natural Science Foundation of Shandong Province (Grant number ZR2020QH201).

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Authors and Affiliations

  1. Department of Nuclear Medicine, Beijing Friendship Hospital Affiliated to Capital Medical University, 95 Yong’an Rd., Xicheng Dist., Beijing, 100050, China

    Cuicui Li, Jun Liu, Xu Yang, Mingyu Zhang & Jigang Yang

  2. Department of Nuclear Medicine, Peking University First Hospital, No. 8 Xishiku Str., Xicheng Dist., Beijing, 100034, China

    Cuicui Li, Qi Yang, Wenpeng Huang & Lei Kang

  3. NHC Key Laboratory of Biotechnology of Antibiotics, Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Courtyard No. 2, Nanwei Rd., Xicheng Dist., Beijing, 100050, China

    Dandan Zhou, Jianhua Gong & Qingfang Miao

  4. Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China

    Rong Wang

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  1. Cuicui Li
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Correspondence to Jianhua Gong, Qingfang Miao, Lei Kang or Jigang Yang.

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Li, C., Liu, J., Yang, X. et al. Theranostic application of 64Cu/177Lu-labeled anti-Trop2 monoclonal antibody in pancreatic cancer tumor models. Eur J Nucl Med Mol Imaging 50, 168–183 (2022). https://doi.org/10.1007/s00259-022-05954-y

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