Journal articles
A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast Cancer
Abstract : 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.
Cited literature [48 references]
https://hal-amu.archives-ouvertes.fr/hal-02297816
Contributor : Brigitte Kerfelec <>
Submitted on : Tuesday, March 31, 2020 - 11:19:34 AM
Last modification on : Wednesday, September 23, 2020 - 4:34:58 AM
Contributor : Brigitte Kerfelec <>
Submitted on : Tuesday, March 31, 2020 - 11:19:34 AM
Last modification on : Wednesday, September 23, 2020 - 4:34:58 AM
File
fimmu-10-01593.pdf
Publication funded by an institution
Licence
Distributed under a Creative Commons Attribution 4.0 International License