Many immunotherapies adapt to solve the field’s most pressing issues (an intricate balance between persistence, potency, and safety) by integrating multiple signaling mechanisms and engaging with more than one target in parallel. With that trend, the binding mechanisms between binder and target also complexify.
Yet, most binding assays haven’t kept up.
Cell Avidity bridges that gap. By measuring the combined strength of cell-cell / cell-protein binding with controlled forces, Cell Avidity generates direct, physiologically relevant measurements of binding in its full, dynamic complexity. Applied to cell or antibody binding research, in experiments on functional modifications or microenvironment modulators, Cell Avidity is shown to reveal the mechanisms of action, facilitating rational design choices, selecting the right candidates fast and early, and ultimately improving therapeutic outcomes.
To support progress in immunotherapy, we need to measure binding the way it happens—in real life, in real cells.
This is Cell Avidity.
Target cells (adherent or non-adherent) are generally of two types:
Introduction of labeled binders to the uniform monolayer. These can include:
Controlled force applied to the bound cells probes the strength of interactions between labeled and target populations.
Fluorescence microscopy captures the number of bound cells before and after force application. The percentage of bound cells after force application indicates the population’s Cell Avidity.
Cell Avidity quantifies cell binding with hundreds of cells per measurement.
Integrating Cell Avidity in the drug development workflow leads to faster identification of the most potent, safe and sensitive drug candidate by reducing the required number of design iterations or eliminating candidates from in vivo preclinical studies which ultimately bind ineffectively in a cellular context.
Quickly rank hundreds to thousands of therapeutic candidates to get insights into sensitivity and safety. Incorporate Cell Avidity early in the discovery workflow helps ensure that only candidates with the most promising binding characteristics progress.
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
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.