A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast Cancer
| Autor: | Del Bano, Joanie, Florès-Florès, Rémy, Josselin, Emmanuelle, Goubard, Armelle, Ganier, Laëtitia, Castellano, Rémy, Chames, Patrick, Baty, Daniel, Kerfelec, Brigitte |
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| Přispěvatelé: | Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Stress Cellulaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), BERNARD, Stéphanie, Kerfelec, Brigitte, This work was supported by institutional grants from INSERM and CNRS and a partnership with GEFLUC. JD was supported by the Assistance Publique des Hôpitaux de Marseille., Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
lcsh:Immunologic diseases. Allergy
[SDV]Life Sciences [q-bio] Immunology Breast Neoplasms Triple Negative Breast Neoplasms [SDV.CAN]Life Sciences [q-bio]/Cancer GPI-Linked Proteins Epitopes multicellular tumor spheroid model (MCTS) [SDV.CAN] Life Sciences [q-bio]/Cancer triple negative breast cancer (TNBC) Cell Line Tumor Antibodies Bispecific mesothelin (MSLN) Humans bispecific antibody (bsAb) Original Research [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology natural killer cells Receptors IgG Antibody-Dependent Cell Cytotoxicity [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy Killer Cells Natural [SDV] Life Sciences [q-bio] Mesothelin Female immunotherapy [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy lcsh:RC581-607 [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| Zdroj: | Frontiers in Immunology Frontiers in Immunology, 2019, 10, pp.1593. ⟨10.3389/fimmu.2019.01593⟩ Frontiers in Immunology, Vol 10 (2019) Frontiers in Immunology, Frontiers, 2019, 10, pp.1593. ⟨10.3389/fimmu.2019.01593⟩ |
| ISSN: | 1664-3224 |
| DOI: | 10.3389/fimmu.2019.01593⟩ |
| Popis: | International audience; Triple negative breast cancers (TNBC) remain a major medical challenge due to poor prognosis and limited treatment options. Mesothelin is a glycosyl-phosphatidyl inositol-linked membrane protein with restricted normal expression and high level expression in a large proportion of TNBC, thus qualifying as an attractive target. Its overexpression in breast tumors has been recently correlated with a decreased disease-free survival and an increase of distant metastases. The objective of the study was to investigate the relevance of a bispecific antibody-based immunotherapy approach through mesothelin targeting and CD16 engagement using a Fab-like bispecific format (MesobsFab). Using two TNBC cell lines with different level of surface mesothelin and epithelial/mesenchymal phenotypes, we showed that, in vitro, MesobsFab promotes the recruitment and penetration of NK cells into tumor spheroids, induces potent dose-dependent cell-mediated cytotoxicity of mesothelin-positive tumor cells, cytokine secretion, and decreases cell invasiveness. MesobsFab was able to induce cytotoxicity in resting human peripheral blood mononuclear cells (PBMC), mainly through its NK cells-mediated antibody dependent cell cytotoxicity (ADCC) activity. In vivo, the anti-tumor effect of MesobsFab depends upon a threshold of MSLN density on target cells. Collectively our data support mesothelin as a relevant therapeutic target for the subset of TNBC that overexpresses mesothelin characterized by a low overall and disease-free survival as well as the potential of MesobsFab as antibody-based immunotherapeutics. |
| Databáze: | OpenAIRE |
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