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Updated: May 25, 2025
A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity
Published on: July 12, 2018
Identification of potent biparatopic antibodies targeting FGFR2 fusion-driven cholangiocarcinoma
Saireudee Chaturantabut1,2,3,4, Sydney Oliver1, Dennie T Frederick1
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Abstract:
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.
Insights
New biparatopic antibodies targeting FGFR2 extracellular domain (ECD) show promise for treating cholangiocarcinoma. These antibodies overcome resistance mechanisms and offer a potential new therapy for FGFR2-altered cancers.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Fibroblast Growth Factor Receptor 2 (FGFR2) gene fusions are prevalent in cholangiocarcinoma.
- Current FGFR kinase inhibitors have limited efficacy due to resistance mutations and adverse effects.
Purpose of the Study:
- To develop novel therapeutics targeting FGFR2.
- To overcome limitations of existing FGFR inhibitors using biparatopic antibodies.
Main Methods:
- Development of biparatopic antibodies targeting distinct epitopes on the FGFR2 extracellular domain (ECD).
- Assessment of antibody efficacy in blocking FGFR2 signaling and cellular transformation.
- In vivo efficacy studies and evaluation of synergy with existing FGFR inhibitors.
Main Results:
- Oncogenic FGFR2 fusions require an intact ECD for transformation.
- Identified biparatopic antibodies effectively inhibit FGFR2 fusion-driven signaling and tumor growth.
- Demonstrated in vivo efficacy, synergy with FGFR inhibitors, and activity against resistant FGFR2 mutations.
Conclusions:
- Biparatopic antibodies targeting FGFR2 ECD are effective against FGFR2-driven cholangiocarcinoma.
- These antibodies offer a potential therapeutic strategy for patients with FGFR2-altered cancers, including those with resistance mutations.
