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Previous studies using antibody and Chimeric Antigen Receptor\u2013T cells (CAR\u2010T) strategies have shown the importance of particular MSLN epitopes for optimal therapeutic response, while other studies have found that certain MSLN\u2010positive tumors can produce proteins that can bind to subsets of IgG1\u2010type antibodies and suppress their immune effector activities. In an attempt to develop an improved anti\u2010MSLN targeting agent, we engineered a humanized divalent anti\u2010MSLN\/anti\u2010CD3\u03b5 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\u2010positive tumor cells. NAV\u2010003 has shown significantly improved tumor cell killing against lines producing immunosuppressive proteins <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. Moreover, NAV\u2010003 demonstrated good tolerability in mice and efficacy against patient\u2010derived mesothelioma xenografts co\u2010engrafted with human peripheral blood mononuclear cells. Together these data support the potential for NAV\u2010003 clinical development and human proof\u2010of\u2010concept studies in patients with MSLN\u2010expressing cancers.<\/jats:p>","DOI":"10.1002\/eji.202250309","type":"journal-article","created":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T19:34:45Z","timestamp":1683315285000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["NAV\u2010003, a bispecific antibody targeting a unique mesothelin epitope and CD3\u03b5 with improved cytotoxicity against humoral immunosuppressed tumors"],"prefix":"10.1002","volume":"53","author":[{"given":"Luigi","family":"Grasso","sequence":"first","affiliation":[{"name":"Navrogen Inc.  Cheyney PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qun","family":"Jiang","sequence":"additional","affiliation":[{"name":"Thoracic and GI Malignancies Branch CCR, NCI, NIH  Bethesda MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffit","family":"Hassan","sequence":"additional","affiliation":[{"name":"Thoracic and GI Malignancies Branch CCR, NCI, NIH  Bethesda MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas C.","family":"Nicolaides","sequence":"additional","affiliation":[{"name":"Navrogen Inc.  Cheyney PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Bradford","family":"Kline","sequence":"additional","affiliation":[{"name":"Navrogen Inc.  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