Identification of potent biparatopic antibodies targeting FGFR2 fusion driven cholangiocarcinoma

Saireudee Chaturantabut; Sydney Oliver; Dennie T. Frederick; Jiwan J. Kim; Foxy P. Robinson; Alessandro Sinopoli; Tian-Yu Song; Yao He; Yuan-Chen Chang; Diego J. Rodriguez; Liang Chang; Devishi Kesar; Meilani Ching; Ruvimbo Dzvurumi; Adel Atari; Yuen-Yi Tseng; Nabeel Bardeesy; William R. Sellers

doi:10.1172/JCI182417

¹Broad Institute of MIT and Harvard, Cambridge, United States of America

²Ridgeline Discovery GmbH, Basel, Switzerland

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

²Ridgeline Discovery GmbH, Basel, Switzerland

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

²Ridgeline Discovery GmbH, Basel, Switzerland

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

²Ridgeline Discovery GmbH, Basel, Switzerland

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

²Ridgeline Discovery GmbH, Basel, Switzerland

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

²Ridgeline Discovery GmbH, Basel, Switzerland

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

²Ridgeline Discovery GmbH, Basel, Switzerland

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

²Ridgeline Discovery GmbH, Basel, Switzerland

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

²Ridgeline Discovery GmbH, Basel, Switzerland

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

²Ridgeline Discovery GmbH, Basel, Switzerland

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

²Ridgeline Discovery GmbH, Basel, Switzerland

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

²Ridgeline Discovery GmbH, Basel, Switzerland

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

²Ridgeline Discovery GmbH, Basel, Switzerland

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¹Broad Institute of MIT and Harvard, Cambridge, United States of America

²Ridgeline Discovery GmbH, Basel, Switzerland

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J Clin Invest. https://doi.org/10.1172/JCI182417.
Copyright © 2025, Chaturantabut et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published February 27, 2025 - Version history

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 sub-optimal 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, biparatopic antibodies may serve as an innovative treatment option for patients with FGFR2-altered cholangiocarcinoma.

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Identification of potent biparatopic antibodies targeting FGFR2 fusion driven cholangiocarcinoma

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