When force met fluorescence: new insights into molecular machines on DNA and chromatin

Translocations involving FGFR2 gene fusions are common in cholangiocarcinoma and gastric carcinoma 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 adverse drug effects.

This webcast will present new work showing that the vast majority of such alterations retain the extracellular domain (ECD), potentially enabling highly selective targeting of the FGFR2 ECD using biotherapeutics.

To improve on the activity of traditional bivalent monotopic antibodies, the Sellers lab systematically generated biparatopic antibodies targeting distinct epitope pairs in FGFR2 ECD, and identified antibodies that effectively block signaling and malignant growth driven by FGFR2-fusions.

These antibodies robustly blocked proliferation and colony formation in FGFR2-fusion driven cholangiocarcinoma and demonstrated robust in vivo anti-tumour activity. In vivo activity was marked by significant antibody-mediated downregulation of FGFR2 and in turn this was associated with robust lysosomal internalization enacted by the two biparatopics. In vitro, the biparatopic antibodies demonstrated activity against FGFR inhibitor resistant alleles of FGFR2. The internalization properties of the antibodies also make them suitable for exploration as antibody-drug conjugates

Learn:

• What are biparatopic antibodies, and how do they improve potency, safety, and tackle resistance mechanisms against membrane receptor targets in solid tumours?
• How do you optimize screening and analytical characterization methods to identify the potent multi-epitope targeting antibodies?
• What is the role of multi-target engagement and multi-epitope design in next-generation antibody therapeutics?

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