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Mechanistic issues limit the effectiveness of many current cancer-targeting antibody therapies, with monospecific antibodies often hindered by receptor dimerization and activation. Biparatopic antibodies, which bind to two unique non-overlapping epitopes, offer a promising solution with stronger binding, more potent antagonism, and higher specificity.
Case study
FGFR2 fusion genes confer sensitivity to FGFR2 kinase inhibitors like Pemigatinib, which saw accelerated FDA approval. However, response rates are hampered by tumor resistance from arising FGRF2 mutations. The researchers showed that the ECD of FGFR2 is necessary for a full oncogenic transformation by FGFR2 fusion. This makes the ECD a promising target for antibody therapies. Biparatopic antibodies present a promising opportunity for targeting FGFR2 owing to increased binding, specificity, and lower likelihood of inter-protein crosslinking. It was hypothesized that the most effective biparatopic antibodies would show both high affinity and high Cell Avidity.
Binding affinity and avidity screening of biparatopic antibodies candidates. Cell Avidity assay shows increased avidity (% bound beads) of biparatopic antibodies (blue/purple) compared to monospecifi c antibodies B, C and D (grey).
Overview of the experimental setup. Left: Visualization of the monospecific antibody epitope sites (A-F) mapped to the FGFR2 extracellular domain (ECD). Center: workflow representation of the generation of the 15 biparatopic antibodies (A/B to E/F) from their monospecific constituent parts (illustrated by F40SL + K409R) by controlled Fab-arm exchange. Right: Viability assay output comparing the 15 biparatopic antibodies with the 6 monospecific antibodies (and an IgG1 negative control) on their growth inhibition of FGFR2-fusion-driven BaF3 cells.
Explore further
Mechanistic issues limit the effectiveness of many current cancer-targeting antibody therapies, with monospecific antibodies often hindered by receptor dimerization and activation. Biparatopic antibodies, which bind to two unique non-overlapping epitopes, offer a promising solution with stronger binding, more potent antagonism, and higher specificity.