NAV‐003, a bispecific antibody targeting a unique mesothelin epitope and CD3ε with improved cytotoxicity against humoral immunosuppressed tumors

Abstract

AbstractMesothelin (MSLN) is a cell surface protein overexpressed in a number of cancer types. Several antibody‐ and cellular‐based MSLN targeting agents have been tested in clinical trials where their therapeutic efficacy has been moderate at best. Previous studies using antibody and Chimeric Antigen Receptor–T cells (CAR‐T) strategies have shown the importance of particular MSLN epitopes for optimal therapeutic response, while other studies have found that certain MSLN‐positive tumors can produce proteins that can bind to subsets of IgG1‐type antibodies and suppress their immune effector activities. In an attempt to develop an improved anti‐MSLN targeting agent, we engineered a humanized divalent anti‐MSLN/anti‐CD3ε bispecific antibody that avoids suppressive factors, can target a MSLN epitope proximal to the tumor cell surface, and is capable of effectively binding, activating, and redirecting T cells to the surface of MSLN‐positive tumor cells. NAV‐003 has shown significantly improved tumor cell killing against lines producing immunosuppressive proteins in vitro and in vivo. Moreover, NAV‐003 demonstrated good tolerability in mice and efficacy against patient‐derived mesothelioma xenografts co‐engrafted with human peripheral blood mononuclear cells. Together these data support the potential for NAV‐003 clinical development and human proof‐of‐concept studies in patients with MSLN‐expressing cancers.