Targeting a membrane-proximal epitope on mesothelin increases the tumoricidal activity of a bispecific antibody blocking CD47 on tumor cells

Abstract

Background: Mesothelin (MSLN) is a cell surface glycoprotein overexpressed and associated with poor prognosis in several human cancers, including mesothelioma, lung- and gastric cancer. While a promising target in cancer, monoclonal antibodies (mAbs) targeting MSLN have demonstrated limited efficacy in clinical trials. In an attempt to incorporate novel modalities to enhance tumor-killing, we have employed a bispecific antibody (biAb) approach that pairs a high affinity anti-MSLN targeting arm to an anti-CD47 arm of an optimized affinity that drives the efficacious binding specifically on MSLN+ cells. CD47 is an innate checkpoint that allows tumor cells to escape immune surveillance through its interaction with signal regulatory protein alpha (SIRPα) on phagocytes. Upregulation of CD47 is correlated with poor prognosis across several cancer types. Here, we tested the tumoricidal activities of CD47xMSLN biAbs targeting different epitopes on MSLN and demonstrated that targeting a membrane proximal epitope was optimal for the tumoricidal activity.