Rapid nanobody-based imaging of mesothelin expressing malignancies compatible with blocking therapeutic antibodies
IntroductionMesothelin (MSLN) is overexpressed in a wide variety of cancers with few therapeutic options and has recently emerged as an attractive target for cancer therapy, with a large number of approaches currently under preclinical and clinical investigation. In this respect, developing mesothel...
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1200652/full |
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| author | Abdennour Benloucif Damien Meyer Laure Balasse Laure Balasse Armelle Goubard Lucile Danner Ahlem Bouhlel Ahlem Bouhlel Rémy Castellano Benjamin Guillet Benjamin Guillet Patrick Chames Brigitte Kerfelec |
| author_facet | Abdennour Benloucif Damien Meyer Laure Balasse Laure Balasse Armelle Goubard Lucile Danner Ahlem Bouhlel Ahlem Bouhlel Rémy Castellano Benjamin Guillet Benjamin Guillet Patrick Chames Brigitte Kerfelec |
| author_sort | Abdennour Benloucif |
| collection | DOAJ |
| description | IntroductionMesothelin (MSLN) is overexpressed in a wide variety of cancers with few therapeutic options and has recently emerged as an attractive target for cancer therapy, with a large number of approaches currently under preclinical and clinical investigation. In this respect, developing mesothelin specific tracers as molecular companion tools for predicting patient eligibility, monitoring then response to mesothelin-targeting therapies, and tracking the evolution of the disease or for real-time visualisation of tumours during surgery is of growing importance.MethodsWe generated by phage display a nanobody (Nb S1) and used enzymatic approaches were used to site-directed conjugate Nb S1 with either ATTO 647N fluorochrome or NODAGA chelator for fluorescence and positron emission tomography imaging (PET) respectively.ResultsWe demonstrated that Nb S1 displays a high apparent affinity and specificity for human mesothelin and demonstrated that the binding, although located in the membrane distal domain of mesothelin, is not impeded by the presence of MUC16, the only known ligand of mesothelin, nor by the therapeutic antibody amatuximab. In vivo experiments showed that both ATTO 647N and [68Ga]Ga-NODAGA-S1 rapidly and specifically accumulated in mesothelin positive tumours compared to mesothelin negative tumours or irrelevant Nb with a high tumour/background ratio. The ex vivo biodistribution profile analysis also confirmed a significantly higher uptake of Nb S1 in MSLN-positive tumours than in MSLNlow tumours.ConclusionWe demonstrated for the first time the use of an anti-MSLN nanobody as PET radiotracer for same day imaging of MSLN+ tumours, targeting an epitope compatible with the monitoring of amatuximab-based therapies and current SS1-derived-drug conjugates. |
| first_indexed | 2024-03-13T05:38:19Z |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-13T05:38:19Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-262bbe933e284b5b9bd890fcc4892a922023-06-14T05:08:07ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-06-011410.3389/fimmu.2023.12006521200652Rapid nanobody-based imaging of mesothelin expressing malignancies compatible with blocking therapeutic antibodiesAbdennour Benloucif0Damien Meyer1Laure Balasse2Laure Balasse3Armelle Goubard4Lucile Danner5Ahlem Bouhlel6Ahlem Bouhlel7Rémy Castellano8Benjamin Guillet9Benjamin Guillet10Patrick Chames11Brigitte Kerfelec12Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, FranceAix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, FranceAix Marseille Univ, CNRS, Centre Européen de Recherche en Imagerie Medicale (CERIMED), Marseille, FranceAix-marseille University, INSERM, INRAE, Centre de recherche en Cardiovasculaire et Nutrition (C2VN), Marseille, FranceAix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, TrGET Preclinical Platform, Marseille, FranceAix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, FranceAix Marseille Univ, CNRS, Centre Européen de Recherche en Imagerie Medicale (CERIMED), Marseille, FranceAix-marseille University, INSERM, INRAE, Centre de recherche en Cardiovasculaire et Nutrition (C2VN), Marseille, FranceAix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, TrGET Preclinical Platform, Marseille, FranceAix Marseille Univ, CNRS, Centre Européen de Recherche en Imagerie Medicale (CERIMED), Marseille, FranceAix-marseille University, INSERM, INRAE, Centre de recherche en Cardiovasculaire et Nutrition (C2VN), Marseille, FranceAix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, FranceAix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, FranceIntroductionMesothelin (MSLN) is overexpressed in a wide variety of cancers with few therapeutic options and has recently emerged as an attractive target for cancer therapy, with a large number of approaches currently under preclinical and clinical investigation. In this respect, developing mesothelin specific tracers as molecular companion tools for predicting patient eligibility, monitoring then response to mesothelin-targeting therapies, and tracking the evolution of the disease or for real-time visualisation of tumours during surgery is of growing importance.MethodsWe generated by phage display a nanobody (Nb S1) and used enzymatic approaches were used to site-directed conjugate Nb S1 with either ATTO 647N fluorochrome or NODAGA chelator for fluorescence and positron emission tomography imaging (PET) respectively.ResultsWe demonstrated that Nb S1 displays a high apparent affinity and specificity for human mesothelin and demonstrated that the binding, although located in the membrane distal domain of mesothelin, is not impeded by the presence of MUC16, the only known ligand of mesothelin, nor by the therapeutic antibody amatuximab. In vivo experiments showed that both ATTO 647N and [68Ga]Ga-NODAGA-S1 rapidly and specifically accumulated in mesothelin positive tumours compared to mesothelin negative tumours or irrelevant Nb with a high tumour/background ratio. The ex vivo biodistribution profile analysis also confirmed a significantly higher uptake of Nb S1 in MSLN-positive tumours than in MSLNlow tumours.ConclusionWe demonstrated for the first time the use of an anti-MSLN nanobody as PET radiotracer for same day imaging of MSLN+ tumours, targeting an epitope compatible with the monitoring of amatuximab-based therapies and current SS1-derived-drug conjugates.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1200652/fullmesothelin (MSLN)nanobodies (Nbs)positron emission tomography - computed tomographyfluorescence imagingdiagnosticsite-directed conjugation |
| spellingShingle | Abdennour Benloucif Damien Meyer Laure Balasse Laure Balasse Armelle Goubard Lucile Danner Ahlem Bouhlel Ahlem Bouhlel Rémy Castellano Benjamin Guillet Benjamin Guillet Patrick Chames Brigitte Kerfelec Rapid nanobody-based imaging of mesothelin expressing malignancies compatible with blocking therapeutic antibodies Frontiers in Immunology mesothelin (MSLN) nanobodies (Nbs) positron emission tomography - computed tomography fluorescence imaging diagnostic site-directed conjugation |
| title | Rapid nanobody-based imaging of mesothelin expressing malignancies compatible with blocking therapeutic antibodies |
| title_full | Rapid nanobody-based imaging of mesothelin expressing malignancies compatible with blocking therapeutic antibodies |
| title_fullStr | Rapid nanobody-based imaging of mesothelin expressing malignancies compatible with blocking therapeutic antibodies |
| title_full_unstemmed | Rapid nanobody-based imaging of mesothelin expressing malignancies compatible with blocking therapeutic antibodies |
| title_short | Rapid nanobody-based imaging of mesothelin expressing malignancies compatible with blocking therapeutic antibodies |
| title_sort | rapid nanobody based imaging of mesothelin expressing malignancies compatible with blocking therapeutic antibodies |
| topic | mesothelin (MSLN) nanobodies (Nbs) positron emission tomography - computed tomography fluorescence imaging diagnostic site-directed conjugation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1200652/full |
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