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

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 Cu-64/Lu-177-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 Cu-64 and Lu-177 radiolabeling respectively. ImmunoPET imaging and RIT studies were performed using Cu-64-NOTA-hIMB1636 and Lu-177-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 Cu-64-NOTA-hIMB1636 and Lu-177-DOTA-hIMB1636 exceeded 95%. PET imaging showed gradually an accumulation of Cu-64-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-Lu-177-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 Cu-64/Lu-177-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.

Automated summary

This study developed Cu-64/Lu-177-labeled anti-Trop2 monoclonal antibody for PET imaging and RIT application in pancreatic cancer tumor models. The results showed that Cu-64-labeled antibody had good accumulation ability in tumor models, and Lu-177-labeled antibody could inhibit the growth of Trop2-overexpressed tumors.