A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast Cancer

Joanie del Bano (1) , Rémy Florès-Florès (2) , Emmanuelle Josselin (1) , Armelle Goubard (1) , Laëtitia Ganier (1) , Rémy Castellano (1) , Patrick Chames (1) , Daniel Baty (1) , Brigitte Kerfelec (1)

1 CRCM - Centre de Recherche en Cancérologie de Marseille
2 IBDM - Institut de Biologie du Développement de Marseille

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.

Keywords: bispecific antibody (bsAb); immunotherapy; mesothelin (MSLN); multicellular tumor spheroid model (MCTS); natural killer cells; triple negative breast cancer (TNBC)

Domains: Life Sciences [q-bio]; Immunology; Immunotherapy

Joanie del Bano, Rémy Florès-Florès, Emmanuelle Josselin, Armelle Goubard, Laëtitia Ganier, et al.. A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast Cancer. Frontiers in Immunology, 2019, 10, pp.1593. ⟨10.3389/fimmu.2019.01593⟩. ⟨hal-02297816⟩