Alternative to Kinase Inhibitors and CytoToxic Agents – AKICYTA

Production of purified recombinant R domain/ Establishment of RPGN model in monkey/ Inhibitory activity of R domain/ Binding of R domain on HB-EGF from kidney sections/ Improvement of binding affinity of R for HB-EGF by mutagenesis/ Proof of concept of protection activity of recombinant R domain in monkey RPGN model/ Further improvement of binding affinity of R for HB-EGF by mutagenesis/ Determination of dose response and therapeutic windiow for R domain/ Assay of R mutants in monkey RPGN model
The development of an original and specific decoy to HB-EGF should offer the opportunity to target this growth factor without affecting other EGFR ligands that are important for the maintenance of the normal skin, lung and digestive tract. Indeed, current strategies inhibiting EGFR are prone to severe side effects. Of note, we have verified that the other EGFR ligands are not involved in experimental RPGN in mice.- We chose to target RPGNs first because of a strong rationale and because of the opportunity for potential accelerated clinical development with European Regulations and Policies in place in favour of rare disease patients.