Rational antibody design for undruggable targets using kinetically controlled biomolecular probes
| Autor: | Anna Reymer, Anders Karlsson, Anaswara Ashok, Emma Johnsson, Jessica Hägglund, Joseph D. Bruton, Roger Karlsson, Kent Jardemark, Sreesha P. Srinivasa, Monica M. Marcus, Niklas Ivarsson, Max Davidson, Alexandra Cavallin, Daniela Papadia, Maria-Nefeli Christakopoulou, Carolina Trkulja, Gavin D. M. Jeffries, Oscar Jungholm, Owe Orwar, Peder Svensson, Gabriella Willman |
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| Rok vydání: | 2021 |
| Předmět: |
Proteases
medicine.drug_class Druggability Computational biology Monoclonal antibody Biochemistry Epitope Epitopes 03 medical and health sciences Transient receptor potential channel 0302 clinical medicine Antigen medicine Humans Antigens Research Articles Ion channel 030304 developmental biology 0303 health sciences Multidisciplinary biology Chemistry SciAdv r-articles Antibodies Monoclonal 030220 oncology & carcinogenesis biology.protein Binding Sites Antibody Antibody Research Article |
| Zdroj: | Science Advances |
| ISSN: | 2375-2548 |
| Popis: | This newly developed biological probes/proteomics method yields functional antibodies targeting previously undruggable targets. 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 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. |
| Databáze: | OpenAIRE |
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