ImmunoPET of trophoblast cell-surface antigen 2 (Trop-2) expression in pancreatic cancer

Chen, Wei-Yu; Younis, Muhsin H.; Barnhart, Todd; Jiang, Dawei; Sun, Tuanwei; Lang, Joshua M.; Engle, Jonathan W.; Zhou, Min; Cai, Weibo

doi:10.1007/s00259-021-05563-1

Cited by 28 publications

(13 citation statements)

References 23 publications

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“…Recently, 89 Zr-labeled anti-Trop2 ( 89 Zr-DFO-AF650) had been used to achieve noninvasively evaluation of Trop2 in both subcutaneous and orthotopic pancreatic cancer tumor models. 89 Zr-DFO-AF650 could e ciently distinguish primary tumors in the orthotopic cancer model, showing high correlation between PET imaging and biodistribution [21]. In our study, 64 Cu-NOTA-IMB1636 in T3M-4 positive group could clearly display the tumor morphology at 4 h p.i., and the tumor uptake reached highest at 48 h about 8.95 ± 1.07%ID/g, which had signi cant differences with T3M-4-blocked and PaTu8988 groups (P < 0.001).…”

Section: Discussionsupporting

confidence: 55%

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

Yang

et al. 2022

Eur J Nucl Med Mol Imaging

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Pancreatic cancer is a malignant tumor with 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 64 Cu/ 177 Lu-labeled anti-Trop2 monoclonal antibody (IMB1636) for positron emission tomography (PET) imaging and radioimmunotherapy (RIT) application in pancreatic cancer tumor models. MethodsThe binding kinetics of IMB1636 to Trop2 was measured by Biolayer interferometry (BLI). Western blotting and ow cytometry were used to screen the Trop2 expression of pancreatic cancer cell lines.IMB1636 were conjugated with p-SCN-Bn-NOTA (NOTA) and DOTA-NHS-ester (DOTA) for 64 Cu and 177 Lu radiolabeling respectively. ImmunoPET imaging and RIT studies were performed using 64 Cu-NOTA-IMB1636 and 177 Lu-DOTA-IMB1636 in subcutaneous pancreatic cancer tumor models. ResultsIMB1636 had strong binding a nity to Trop2 according to the results of BLI. T3M-4 cell line showed strongest expression of Trop2 and speci c binding ability of IMB1636. The radiochemical purity of 64 Cu-NOTA-IMB1636 and 177 Lu-DOTA-IMB1636 exceeded 95%. PET imaging showed gradually accumulation of 64 Cu-NOTA-IMB1636 in T3M-4 tumor models. The peak tumor uptake was 8.95 ± 1.07%ID/g (n = 4) at 48 h post injection (p.i.), which had signi cant differences with T3M-4-blocked and PaTu8988 negative groups (P < 0.001). High dose 177 Lu-DOTA-IMB1636 demonstrated strongest tumor suppression with standardized tumor volume about 94.24 ± 14.62% (n = 5) at 14 days p.i., signi cantly smaller than other groups (P = 0.000 ~ 0.047). Ex vivo Biodistribution and histological staining veri ed the in vivo PET imaging and RIT results. ConclusionsThis study demonstrated that 64 Cu/ 177 Lu labeled IMB1636 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 strati cation and management of pancreatic cancer patients.

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Section: Discussionsupporting

confidence: 55%

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

Yang

et al. 2022

Eur J Nucl Med Mol Imaging

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“…Therefore, immunoPET probes designed for PDAC must avoid significant uptake by the liver. Since mAbs are mainly degraded and cleared from the hepatobiliary system, a portion of the mAb-based immunoPET probes in previous studies had significant uptake in the liver, − making it more difficult to identify PDAC liver metastasis. Previously, an anti-CD47 mAb was used for immunoPET in xenograft tumor models, but it had high retention in the liver, spleen, and kidneys .…”

Section: Discussionmentioning

confidence: 99%

ImmunoPET Imaging of CD47 with VHH-Derived Tracers in Pancreatic Cancers

et al. 2023

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Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with insidious onset, rapid progression, and a very poor prognosis. CD47 is a transmembrane protein associated with the development and poor prognosis of pancreatic cancer. The aim of this study was to evaluate the diagnostic value of novel immunoPET tracers targeting CD47 in preclinical pancreatic cancer models. The association of CD47 expression with pancreatic cancer was analyzed using the Gene Expression Profiling Interactive Analysis platform. Immunohistochemical analysis of tissue microarrays was performed to detect CD47 expression in PDAC. CD47 expression levels on BxPC-3 and AsPC-1 cell membranes were compared using flow cytometry. A VHH (C2)targeting human CD47 and its albumin-binding derivative (ABDC2) were labeled with 68 Ga or 89 Zr, respectively. The developed tracers were evaluated by immuno-positron emission tomography (immunoPET) imaging in tumor-bearing nude and CD47-humanized mice.[ 68 Ga]Ga-NOTA-C2 effectively detected tumor lesions in nude mice models and further showed confirmative imaging capacity in CD47-humanized PDAC models. Compared with [ 68 Ga]Ga-NOTA-C2, [ 89 Zr]Zr-DFO-ABDC2 had a significantly prolonged circulation time, increased tumor uptake, and reduced accumulation in the kidneys. Finally, biodistribution and histological staining confirmed the results of the immunoPET imaging studies. In this study, we validated that two novel VHH-derived molecular imaging tracers for immunoPET imaging ([ 68 Ga]Ga-NOTA-C2 and [ 89 Zr]Zr-DFO-ABDC2) can effectively annotate CD47 expression and diagnose PDAC in a target-specific manner. Clinical application of the imaging strategies may help select patients for CD47-targeted therapies and assess the response thereafter.

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“…Due to the ubiquitous expression in cancer cells with a relatively low expression in most normal tissues, Trop-2 represents an excellent candidate as diagnostic [ 50 , 51 , 52 ] and a therapeutic target, specifically for antibody-based therapy. Nevertheless, relevant toxicities have been reported relating to the role of Trop-2 in healthy tissues [ 37 ].…”

Section: Strategies To Target Trop-2mentioning

confidence: 99%

Overview of Trop-2 in Cancer: From Pre-Clinical Studies to Future Directions in Clinical Settings

Lombardi

Filetti

Falcone

et al. 2023

Cancers

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Trophoblast cell surface antigen-2 (Trop-2) is a glycoprotein that was first described as a membrane marker of trophoblast cells and was associated with regenerative abilities. Trop-2 overexpression was also described in several tumour types. Nevertheless, the therapeutic potential of Trop-2 was widely recognized and clinical studies with drug–antibody conjugates have been initiated in various cancer types. Recently, these efforts have been rewarded with the approval of sacituzumab govitecan from both the Food and Drug Administration (FDA) and European Medicines Agency (EMA), for metastatic triple-negative breast cancer patients. In our work, we briefly summarize the various characteristics of cancer cells overexpressing Trop-2, the pre-clinical activities of specific inhibitors, and the role of anti-Trop-2 therapy in current clinical practice. We also review the ongoing clinical trials to provide a snapshot of the future developments of these therapies.

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ImmunoPET of trophoblast cell-surface antigen 2 (Trop-2) expression in pancreatic cancer

Cited by 28 publications

References 23 publications

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

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

ImmunoPET Imaging of CD47 with VHH-Derived Tracers in Pancreatic Cancers

Overview of Trop-2 in Cancer: From Pre-Clinical Studies to Future Directions in Clinical Settings

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