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Updated: Jun 11, 2025
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
Identification of potent biparatopic antibodies targeting FGFR2 fusion driven cholangiocarcinoma
Abstract:
Translocations involving FGFR2 gene fusions are common in cholangiocarcinoma and predict response to FGFR kinase inhibitors. However, the rate and durability of response are limited due to the emergence of resistance, typically involving acquired FGFR2 kinase domain mutations, and to sub-optimal dosing, relating to drug adverse effects. Here, we report the development of biparatopic antibodies targeting the FGFR2 extracellular domain (ECD), as candidate therapeutics. Biparatopic antibodies can overcome drawbacks of standard bivalent monoparatopic 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 that target distinct epitope pairs along the 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 new treatment options for patients with FGFR2-altered cholangiocarcinoma.
Summary:
We identify biparatopic FGFR2 antibodies that are effective against FGFR2 fusion driven cholangiocarcinoma.
Insights
New biparatopic antibodies targeting FGFR2 extracellular domain show promise for treating cholangiocarcinoma. These therapies are effective against FGFR2 fusions and overcome resistance mechanisms, offering new hope for patients.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Fibroblast Growth Factor Receptor 2 (FGFR2) gene fusions are prevalent in cholangiocarcinoma, predicting response to FGFR kinase inhibitors.
- Treatment limitations include emergent resistance mutations and adverse effects from suboptimal dosing of current therapies.
Purpose of the Study:
- To develop novel therapeutic antibodies targeting the FGFR2 extracellular domain (ECD) for cholangiocarcinoma.
- To investigate the efficacy of biparatopic antibodies in overcoming resistance and improving treatment outcomes.
Main Methods:
- Systematic generation and screening of biparatopic antibodies targeting distinct FGFR2 ECD epitopes.
- Assessment of antibody efficacy in blocking FGFR2 signaling and inhibiting oncogenic transformation in vitro.
- Evaluation of in vivo efficacy, synergy with existing inhibitors, and activity against resistant FGFR2 mutations.
Main Results:
- Oncogenic transformation driven by FGFR2 fusions requires an intact ECD.
- Identified biparatopic antibodies effectively block FGFR2 signaling and malignant growth.
- Demonstrated in vivo efficacy, synergy with FGFR inhibitors, and activity against FGFR2 fusions with kinase domain mutations.
Conclusions:
- Biparatopic antibodies targeting the FGFR2 ECD are effective against FGFR2 fusion-driven cholangiocarcinoma.
- These antibodies offer a potential therapeutic strategy to overcome resistance and improve patient outcomes.
