Abstract 5666: NAV-003, a full-length IgG1 bispecific antibody targeting a unique mesothelin epitope and CD3 to improve cytotoxicity against humoral immunosuppressed tumors

Abstract Mesothelin (MSLN) is a cell surface protein over-expressed 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 CAR-T based agents have shown the importance of particular MSLN epitopes for optimal therapeutic response, while other studies have found 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 a more optimized anti-MSLN targeting agent, we engineered a humanized divalent anti-MSLN/anti-CD3ε bispecific antibody called NAV-003 that targets a MSLN epitope proximal to the tumor cell surface and an anti-CD3ε single-chain antibody capable of effectively binding, activating and directing T-cells to the surface of MSLN-bound 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 and efficacy against patient-derived mesothelioma xenograft models 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. Citation Format: Luigi Grasso, Qun Jiang, Raffit Hassan, Nicholas C. Nicolaides, J. Bradford Kline. NAV-003, a full-length IgG1 bispecific antibody targeting a unique mesothelin epitope and CD3 to improve cytotoxicity against humoral immunosuppressed tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5666.