A multimodal molecular imaging approach targeting urokinase plasminogen activator receptor for the diagnosis, resection and surveillance of urothelial cell carcinoma

Baart, Victor M.; Horst, Geertje van der; Deken, Marion M.; Bhairosingh, Shadhvi S.; Schomann, Timo; Sier, Vincent Q.; Mark, Maaike H. van der; Iamele, Luisa; Jonge, Hugo de; Resnati, Massimo; Mazar, Andrew P.; Pelger, Rob C.M.; Pluijm, Gabri van der; Kuppen, Peter J.K.; Vahrmeijer, Alexander L.; Sier, C.F.M.

doi:10.1016/j.ejca.2021.01.001

Cited by 8 publications

(14 citation statements)

References 40 publications

(45 reference statements)

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“…As uPAR expression is highest at the tumor borders, our group has primarily focused on developing uPAR-targeted FGS tracers. We have successfully targeted uPAR for FGS in various in vivo human cancer models using a mouse monoclonal antibody and more recently with MNPR-101, a firstin-class humanized monoclonal antibody targeting domain 800CW-NHS ester (from here on 800F; LI-COR biotechnology, Lincoln, USA) according to the manufacturer and as published before [16]. Digestion and conjugation results were evaluated using SDS-PAGE on pre-casted 4-20% gels (Criterion, Bio-Rad laboratories, Veenendaal, The Netherlands).…”

Section: Introductionmentioning

confidence: 99%

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Side-by-Side Comparison of uPAR-Targeting Optical Imaging Antibodies and Antibody Fragments for Fluorescence-Guided Surgery of Solid Tumors

et al. 2021

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Purpose Radical resection is paramount for curative oncological surgery. Fluorescence-guided surgery (FGS) aids in intraoperative identification of tumor-positive resection margins. This study aims to assess the feasibility of urokinase plasminogen activator receptor (uPAR) targeting antibody fragments for FGS in a direct comparison with their parent IgG in various relevant in vivo models. Procedures Humanized anti-uPAR monoclonal antibody MNPR-101 (uIgG) was proteolytically digested into F(ab’)2 and Fab fragments named uFab2 and uFab. Surface plasmon resonance (SPR) and cell assays were used to determine in vitro binding before and after fluorescent labeling with IRDye800CW. Mice bearing subcutaneous HT-29 human colonic cancer cells were imaged serially for up to 120 h after fluorescent tracer administration. Imaging characteristics and ex vivo organ biodistribution were further compared in orthotopic pancreatic ductal adenocarcinoma (BxPc-3-luc2), head-and-neck squamous cell carcinoma (OSC-19-luc2-GFP), and peritoneal carcinomatosis (HT29-luc2) models using the clinical Artemis fluorescence imaging system. Results Unconjugated and conjugated uIgG, uFab2, and uFab specifically recognized uPAR in the nanomolar range as determined by SPR and cell assays. Subcutaneous tumors were clearly identifiable with tumor-to-background ratios (TBRs) > 2 after 72 h for uIgG-800F and 24 h for uFab2-800F and uFab-800F. For the latter two, mean fluorescence intensities (MFIs) dipped below predetermined threshold after 72 h and 36 h, respectively. Tumors were easily identified in the orthotopic models with uIgG-800F consistently having the highest MFIs and uFab2-800F and uFab-800F having similar values. In biodistribution studies, kidney and liver fluorescence approached tumor fluorescence after uIgG-800F administration and surpassed tumor fluorescence after uFab2-800F or uFab-800F administration, resulting in interference in the abdominal orthotopic mouse models. Conclusions In a side-by-side comparison, FGS with uPAR-targeting antibody fragments compared with the parent IgG resulted in earlier tumor visualization at the expense of peak fluorescence intensity.

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Section: Introductionmentioning

confidence: 99%

“…three of uPAR [14][15][16]. This domain is ideal as recognition is independent of the often simultaneously upregulated uPARligands urokinase and vitronectin, and remains membrane bound when uPAR is cleaved [9].…”

mentioning

confidence: 99%

Side-by-Side Comparison of uPAR-Targeting Optical Imaging Antibodies and Antibody Fragments for Fluorescence-Guided Surgery of Solid Tumors

et al. 2021

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“…In the recent 5 years, NIR-I fluorophores in the reported bimodal FI/PAI probes are often served as the CAs of PAI as well. These fluorophores, including natural origin ( Zhou et al, 2017 ; Zheng et al, 2018 ; Siwawannapong et al, 2020 ), cyanine derivatives ( Baart et al, 2021 ; Doan et al, 2021 ; Mu et al, 2021 ; Nishio et al, 2021 ), and other types of organic dyes ( Park et al, 2020 ; Shin et al, 2021 ; Wang et al, 2022 ), had strong and broad optical absorption in the NIR-I region to provide PA signals. Apart from the broad applications of the traditional cyanine dyes, researchers have devoted much attention to developing new structures to obtain better absorption and emission properties in this field.…”

Section: Bimodal Imaging Of Tumor Based On Near-infrared-i Fluorescencementioning

confidence: 99%

NIR-I Dye-Based Probe: A New Window for Bimodal Tumor Theranostics

et al. 2022

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Near-infrared (NIR, 650–1700 nm) bioimaging has emerged as a powerful strategy in tumor diagnosis. In particular, NIR-I fluorescence imaging (650–950 nm) has drawn more attention, benefiting from the high quantum yield and good biocompatibility. Since their biomedical applications are slightly limited by their relatively low penetration depth, NIR-I fluorescence imaging probes have been under extensive development in recent years. This review summarizes the particular application of the NIR-I fluorescent dye-contained bimodal probes, with emphasis on related nanoprobes. These probes have enabled us to overcome the drawbacks of individual imaging modalities as well as achieve synergistic imaging. Meanwhile, the application of these NIR-I fluorescence-based bimodal probes for cancer theranostics is highlighted.

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“…(C) NIR and merged images recorded 3 days post iv injection of 1 nmol IRDye800CW–ATN658 (a humanized monoclonal anti-uPAR antibody) in a orthotropic mouse model of urothelial cell carcinoma. (A,B) were reproduced and modified from Kurbegovic et al (2021) and (C) from Baart et al (2021) according to the CC-BY license.…”

Section: In Vivo Targeting Of Upar In Non-invasive Imaging Modalitiesmentioning

confidence: 99%

“…Besides peptide-based targeting of uPAR—the topic of this review—several macromolecular uPAR-targeting moieties have been developed for optical imaging and therapeutic targeting including (i) monoclonal anti-uPAR antibodies ( Figure 4C ; LeBeau et al, 2014 ; Boonstra et al, 2015 ; Baart et al, 2021 ) and (ii) various nanoparticles carrying receptor binding fragments of uPA (ATF) or peptide derivatives (AE105) ( Hansen et al, 2007 ; Yang et al, 2013 ; Gao et al, 2017 ; Zuo et al, 2020 ). Due to the inherently long “washout times” (days rather than hours) needed for these probes to reach maximal TBR, they are probably less suited in the daily clinical workflow as imaging modalities, but they are optimally suited for targeted delivery of cytotoxic payloads.…”

Section: In Vivo Targeting Of Upar In Non-invasive Imaging Modalitiesmentioning

confidence: 99%

Targeting the Urokinase-Type Plasminogen Activator Receptor (uPAR) in Human Diseases With a View to Non-invasive Imaging and Therapeutic Intervention

Leth

Ploug

2021

Front. Cell Dev. Biol.

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The interaction between the serine protease urokinase-type plasminogen activator (uPA) and its glycolipid-anchored receptor (uPAR) focalizes plasminogen activation to cell surfaces, thereby regulating extravascular fibrinolysis, cell adhesion, and migration. uPAR belongs to the Ly6/uPAR (LU) gene superfamily and the high-affinity binding site for uPA is assembled by a dynamic association of its three consecutive LU domains. In most human solid cancers, uPAR is expressed at the invasive areas of the tumor-stromal microenvironment. High levels of uPAR in resected tumors or shed to the plasma of cancer patients are robustly associated with poor prognosis and increased risk of relapse and metastasis. Over the years, a plethora of different strategies to inhibit uPA and uPAR function have been designed and investigated in vitro and in vivo in mouse models, but so far none have been implemented in the clinics. In recent years, uPAR-targeting with the intent of cytotoxic eradication of uPAR-expressing cells have nonetheless gained increasing momentum. Another avenue that is currently being explored is non-invasive imaging with specific uPAR-targeted reporter-molecules containing positron emitting radionuclides or near-infrared (NIR) florescence probes with the overarching aim of being able to: (i) localize disease dissemination using positron emission tomography (PET) and (ii) assist fluorescence guided surgery using optical imaging. In this review, we will discuss these advancements with special emphasis on applications using a small 9-mer peptide antagonist that targets uPAR with high affinity.

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A multimodal molecular imaging approach targeting urokinase plasminogen activator receptor for the diagnosis, resection and surveillance of urothelial cell carcinoma

Cited by 8 publications

References 40 publications

Side-by-Side Comparison of uPAR-Targeting Optical Imaging Antibodies and Antibody Fragments for Fluorescence-Guided Surgery of Solid Tumors

Side-by-Side Comparison of uPAR-Targeting Optical Imaging Antibodies and Antibody Fragments for Fluorescence-Guided Surgery of Solid Tumors

NIR-I Dye-Based Probe: A New Window for Bimodal Tumor Theranostics

Targeting the Urokinase-Type Plasminogen Activator Receptor (uPAR) in Human Diseases With a View to Non-invasive Imaging and Therapeutic Intervention

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