Oblique Therapeutics AB, SE-41346 Gothenburg, Sweden.
Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Sci Adv. 2021 Apr 16;7(16). doi: 10.1126/sciadv.abe6397. Print 2021 Apr.
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.
几种重要的药物靶点，如离子通道和 G 蛋白偶联受体，用当前的抗体技术很难接近。为了针对这些靶点类别，我们探索了动力学控制的蛋白酶作为结构动力学敏感的药物靶标在天然状态和疾病相关的蛋白质。通过使用低雷诺数流，使得进行单次或几次蛋白酶切割，我们可以鉴定出抗体结合位点（抗原表位），并将其转化为短序列抗原用于抗体生产。我们获得了表位-抗位区域的分子水平信息，并可以生产针对难以药物靶标的具有编程药理学功能的高亲和力抗体。我们展示了针对瞬时受体电位香草素 1（TRPV1）通道的首个刺激选择性单克隆抗体，该通道是一种经过临床验证的疼痛靶点，被广泛认为无法用抗体治疗，以及凋亡诱导抗体选择性地介导 KRAS 突变细胞中的细胞毒性。我们希望这个平台将拓宽抗体治疗的范围，使患者受益。
