A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast Cancer
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 qualifyin...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.01593/full |
| _version_ | 1819085521375199232 |
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| author | Joanie Del Bano Rémy Florès-Florès Emmanuelle Josselin Armelle Goubard Laetitia Ganier Rémy Castellano Patrick Chames Daniel Baty Brigitte Kerfelec |
| author_facet | Joanie Del Bano Rémy Florès-Florès Emmanuelle Josselin Armelle Goubard Laetitia Ganier Rémy Castellano Patrick Chames Daniel Baty Brigitte Kerfelec |
| author_sort | Joanie Del Bano |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T21:05:41Z |
| format | Article |
| id | doaj.art-e903097211f846678847b4f060e65053 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-21T21:05:41Z |
| publishDate | 2019-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-e903097211f846678847b4f060e650532022-12-21T18:50:18ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-07-011010.3389/fimmu.2019.01593442715A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast CancerJoanie Del Bano0Rémy Florès-Florès1Emmanuelle Josselin2Armelle Goubard3Laetitia Ganier4Rémy Castellano5Patrick Chames6Daniel Baty7Brigitte Kerfelec8Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, FranceAix Marseille Univ, CNRS, Institut de Biologie du Développement de Marseille, UMR7288, Marseille, FranceAix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, FranceAix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, FranceAix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, FranceAix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, FranceAix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, FranceAix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, FranceAix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, FranceTriple 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.https://www.frontiersin.org/article/10.3389/fimmu.2019.01593/fullbispecific antibody (bsAb)natural killer cellsimmunotherapytriple negative breast cancer (TNBC)mesothelin (MSLN)multicellular tumor spheroid model (MCTS) |
| spellingShingle | Joanie Del Bano Rémy Florès-Florès Emmanuelle Josselin Armelle Goubard Laetitia Ganier Rémy Castellano Patrick Chames Daniel Baty Brigitte Kerfelec A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast Cancer Frontiers in Immunology bispecific antibody (bsAb) natural killer cells immunotherapy triple negative breast cancer (TNBC) mesothelin (MSLN) multicellular tumor spheroid model (MCTS) |
| title | A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast Cancer |
| title_full | A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast Cancer |
| title_fullStr | A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast Cancer |
| title_full_unstemmed | A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast Cancer |
| title_short | A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast Cancer |
| title_sort | bispecific antibody based approach for targeting mesothelin in triple negative breast cancer |
| topic | bispecific antibody (bsAb) natural killer cells immunotherapy triple negative breast cancer (TNBC) mesothelin (MSLN) multicellular tumor spheroid model (MCTS) |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.01593/full |
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