| Autor: |
Del Bano J; Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, France., Florès-Florès R; Aix Marseille Univ, CNRS, Institut de Biologie du Développement de Marseille, UMR7288, Marseille, France., Josselin E; Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, France., Goubard A; Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, France., Ganier L; Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, France., Castellano R; Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, France., Chames P; Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, France., Baty D; Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, France., Kerfelec B; Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmette, CRCM, Marseille, France. |
| Abstrakt: |
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. |
