Rational antibody design for undruggable targets using kinetically controlled biomolecular probes

Carolina L. Trkulja, Oscar Jungholm, Max Davidson, Kent Jardemark, Monica M. Marcus, Jessica Hägglund, Anders Karlsson, Roger Karlsson, Joseph Bruton, Niklas Ivarsson, Sreesha P. Srinivasa, Alexandra Cavallin (+9 others)
2021 Science Advances  
Several important drug targets, e.g., ion channels and G protein–coupled receptors, are extremely difficult to approach with current antibody technologies. To address these targets classes, we explored kinetically controlled proteases as structural dynamics–sensitive druggability probes in native-state and disease-relevant proteins. By using low–Reynolds number flows, such that a single or a few protease incisions are made, we could identify antibody binding sites (epitopes) that were
more » ... that were translated into short-sequence antigens for antibody production. We obtained molecular-level information of the epitope-paratope region and could produce high-affinity antibodies with programmed pharmacological function against difficult-to-drug targets. We demonstrate the first stimulus-selective monoclonal antibodies targeting the transient receptor potential vanilloid 1 (TRPV1) channel, a clinically validated pain target widely considered undruggable with antibodies, and apoptosis-inducing antibodies selectively mediating cytotoxicity in KRAS-mutated cells. It is our hope that this platform will widen the scope of antibody therapeutics for the benefit of patients.
doi:10.1126/sciadv.abe6397 pmid:33863724 fatcat:ubwbmvb6nzfwndgafg6nzrl66m