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

Joanie Del Bano,Daniel Baty,Patrick Chames,Brigitte Kerfelec,Laetitia Ganier,Rémy Florès-Florès,Rémy Castellano,Emmanuelle Josselin,Armelle Goubard

doi:10.3389/fimmu.2019.01593

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.

Highlights

Over the past 15 years, the enrichment of the diagnosis and therapeutic arsenal against breast cancers has undoubtedly contributed to improving their prognosis
Binding properties of MesobsFab were investigated by flow cytometry on HCC1806 cell line and on human CD16-transfected Jurkat cells (Figure S1)
Despite a significant overall decrease in breast cancer-related mortality explained by major improvements in early detection and therapeutic strategies, triple negative breast cancers which are clinically defined by the absence of hormonal and HER2 receptors, remain a clinical challenge with limited therapeutic options and the worse overall survival

Summary

Introduction

Over the past 15 years, the enrichment of the diagnosis and therapeutic arsenal against breast cancers has undoubtedly contributed to improving their prognosis. Despite these advances, recurrences still occur and metastatic breast cancer remains in most cases an incurable disease. TNBC which represent 10–20% of invasive breast cancers account for the majority of deaths in breast cancer patients due to a higher recurrence rate and a worse overall survival rate than other subtypes of breast cancer [1]. Apart from their aggressiveness and their ability to rapidly. The development of new strategies and/or new therapeutic molecules for these dark prognosis cancers is a major clinical challenge

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