{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T07:44:31Z","timestamp":1777880671710,"version":"3.51.4"},"reference-count":50,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T00:00:00Z","timestamp":1741651200000},"content-version":"unspecified","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["SNSF 310030"],"award-info":[{"award-number":["SNSF 310030"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Ludwig Cancer Research","award":["Not applicable (no award number)"],"award-info":[{"award-number":["Not applicable (no award number)"]}]},{"name":"Fondazione Teofilo Rossi di Montelera e di Premuda","award":["Not applicable (no award number)"],"award-info":[{"award-number":["Not applicable (no award number)"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,2,23]]},"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The glycosylphosphatidylinositol-anchored cell surface protein mesothelin (MSLN) shows elevated expression in many malignancies and is an established clinical-stage target for antibody-directed therapeutic strategies. Of these, the harnessing of autologous patient T cells via engineered anti-MSLN chimeric antigen receptors (CAR-T) is an approach garnering considerable interest. Although generally shown to target tumor MSLN safely, CAR-T trials have failed to deliver the impressive curative or response metrics achieved for hematological malignancies using the same technology. A need exists, therefore, for improved anti-MSLN molecules and\/or more optimal ways to leverage immune effector cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We performed ELISA, label-free kinetic binding assays, FACS, Western blotting, and transient recombinant MSLN expression to characterize the recognition properties of a novel CAR-active human scFv clone, LABC-13F08. To investigate T cell redirection, we conducted kinetic IncuCyte co-culture killing assays using transduced primary T cells and MSLN<jats:sup>+<\/jats:sup> target cell lines and assessed levels of activation markers and effector cytokines. The antitumor potential of LABC-13F08 formatted as a bispecific engager (BiTE) was evaluated in vivo using transduced human primary T cells and immunocompromised NSG mice xenografted with ovarian, mesothelioma, and pancreatic MSLN<jats:sup>+<\/jats:sup> tumor cell lines.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The LABC-13F08 scFv is highly unusual and distinct from existing (pre)clinical anti-MSLN antibody fragments, exhibiting an absolute requirement for divalent cations to drive MSLN recognition. As a monovalent BiTE, LABC-13F08 demonstrates robust in vitro potency. Additionally, primary human T cells engineered for constitutive secretion of the 13F08 BiTE exhibit strong antitumor activity toward in vivo ovarian and mesothelioma xenograft models and show encouraging levels of monotherapy control in a challenging pancreatic model. LABC-13F08 BiTE secreted from engineered T cells (BiTE-T) can both recruit non-engineered bystander T cells and also induce activation-dependent MSLN-independent bystander killing of cells lacking cognate antigen. To address safety concerns, 13F08 BiTE-T cells can be rapidly targeted for clearance via a molecular \u201coff\u201d switch.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The novel LABC-13F08 scFv exhibits a mode of binding to MSLN which is not observed in typical anti-MSLN antibodies. Efficacious targeting by a T cell secreted engager would represent a clinically differentiated approach for the treatment of MSLN<jats:sup>+<\/jats:sup> tumors.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2024-010063","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T08:25:56Z","timestamp":1741854356000},"page":"e010063","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Potent and durable control of mesothelin-expressing tumors by a novel T cell-secreted bi-specific engager"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct06756035","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06255665","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03872206","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Paris","family":"Kosti","sequence":"first","affiliation":[{"name":"Department of Oncology, Ludwig Cancer Research Lausanne Branch, University of Lausanne, Lausanne, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johan","family":"Abram-Saliba","sequence":"additional","affiliation":[{"name":"Department of Oncology, Ludwig Cancer Research Lausanne Branch, University of Lausanne, Lausanne, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laetitia","family":"Pericou-Troquier","sequence":"additional","affiliation":[{"name":"Department of Oncology, Ludwig Cancer Research Lausanne Branch, University of 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Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6849-7194","authenticated-orcid":false,"given":"Melita","family":"Irving","sequence":"additional","affiliation":[{"name":"Department of Oncology, Ludwig Cancer Research Lausanne Branch, University of Lausanne, Lausanne, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Coukos","sequence":"additional","affiliation":[{"name":"Department of Oncology, Ludwig Cancer Research Lausanne Branch, University of Lausanne, Lausanne, Switzerland"},{"name":"Department of Oncology, CHUV, Lausanne, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8194-5414","authenticated-orcid":false,"given":"Evripidis","family":"Lanitis","sequence":"additional","affiliation":[{"name":"Department of Oncology, Ludwig Cancer Research Lausanne Branch, University of Lausanne, Lausanne, 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