{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T23:55:03Z","timestamp":1788998103265,"version":"build-2803163510"},"reference-count":55,"publisher":"American Society for Clinical Investigation","issue":"8","license":[{"start":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T00:00:00Z","timestamp":1744675200000},"content-version":"vor","delay-in-days":47,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"US Department of Defense, Health Program Congressionally Directed Medical Research Programs (CDMRP), Peer Reviewed Cancer Research Program Translational Team Science Award","award":["W81XWH-21-PRCRP-TTS"],"award-info":[{"award-number":["W81XWH-21-PRCRP-TTS"]}]},{"name":"the Cholangiocarcinoma Foundation","award":["Andrea Lynn Scott Memorial Research Fellowship"],"award-info":[{"award-number":["Andrea Lynn Scott Memorial Research Fellowship"]}]},{"name":"National Cancer Institute","award":["R01CA233626"],"award-info":[{"award-number":["R01CA233626"]}]},{"name":"US Department of Defense, Health Program Congressionally Directed Medical Research Programs","award":["W81XWH-20-1-0325"],"award-info":[{"award-number":["W81XWH-20-1-0325"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,15]]},"abstract":"<jats:p>Translocations involving FGFR2 gene fusions are common in cholangiocarcinoma and predict response to FGFR kinase inhibitors. However, response rates and durability are limited due to the emergence of resistance, typically involving FGFR2 kinase domain mutations, and to suboptimal dosing, relating to drug adverse effects. Here, we develop biparatopic antibodies targeting the FGFR2 extracellular domain (ECD) as candidate therapeutics. Biparatopic antibodies can overcome drawbacks of bivalent monospecific antibodies, which often show poor inhibitory or even agonist activity against oncogenic receptors. We show that oncogenic transformation by FGFR2 fusions requires an intact ECD. Moreover, by systematically generating biparatopic antibodies targeting distinct epitope pairs in FGFR2 ECD, we identified antibodies that effectively block signaling and malignant growth driven by FGFR2 fusions. Importantly, these antibodies demonstrate efficacy in vivo, synergy with FGFR inhibitors, and activity against FGFR2 fusions harboring kinase domain mutations. Thus, we believe that biparatopic antibodies may serve as an innovative treatment option for patients with FGFR2-altered cholangiocarcinoma.<\/jats:p>","DOI":"10.1172\/jci182417","type":"journal-article","created":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T12:00:17Z","timestamp":1740657617000},"source":"Crossref","is-referenced-by-count":6,"title":["Identification of potent biparatopic antibodies targeting FGFR2 fusion\u2013driven cholangiocarcinoma"],"prefix":"10.1172","volume":"135","author":[{"given":"Saireudee","family":"Chaturantabut","sequence":"first","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."},{"name":"Dana-Farber Cancer Institute, Boston, Massachusetts, USA."},{"name":"Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 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