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

Cuicui Li; Jun Liu; Xu Yang; Qi Yang; Wenpeng Huang; Mingyu Zhang; Dandan Zhou; Rong Wang; Jianhua Gong; Qingfang Miao; Lei Kang; Jigang Yang

doi:10.1007/s00259-022-05954-y

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

Eur J Nucl Med Mol Imaging. 2022 Dec;50(1):168-183. doi: 10.1007/s00259-022-05954-y. Epub 2022 Sep 5.

Authors

Cuicui Li^{1

2}, Jun Liu¹, Xu Yang¹, Qi Yang², Wenpeng Huang², Mingyu Zhang¹, Dandan Zhou³, Rong Wang⁴, Jianhua Gong⁵, Qingfang Miao⁵, Lei Kang⁶, Jigang Yang⁷

Affiliations

¹ Department of Nuclear Medicine, Beijing Friendship Hospital Affiliated to Capital Medical University, 95 Yong'an Rd., Xicheng Dist., Beijing, 100050, China.
² Department of Nuclear Medicine, Peking University First Hospital, No. 8 Xishiku Str., Xicheng Dist., Beijing, 100034, China.
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.
⁴ Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
⁵ 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. miaoqf@imb.pumc.edu.cn.
⁶ Department of Nuclear Medicine, Peking University First Hospital, No. 8 Xishiku Str., Xicheng Dist., Beijing, 100034, China. kanglei@bjmu.edu.cn.
⁷ Department of Nuclear Medicine, Beijing Friendship Hospital Affiliated to Capital Medical University, 95 Yong'an Rd., Xicheng Dist., Beijing, 100050, China. yangjigang@ccmu.edu.cn.

PMID: 36063202
DOI: 10.1007/s00259-022-05954-y

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.

Keywords: Cu-64; ImmunoPET; Lu-177; Pancreatic cancer; Radioimmunotherapy (RIT); Trop2.

MeSH terms

Antibodies, Monoclonal / metabolism
Antibodies, Monoclonal / therapeutic use
Cell Line, Tumor
Humans
Pancreatic Neoplasms* / diagnostic imaging
Pancreatic Neoplasms* / radiotherapy
Positron-Emission Tomography / methods
Precision Medicine*
Tissue Distribution

Substances

Antibodies, Monoclonal