Development of a novel class of ion channel blockers for the treatment of autoimmune disease

开发一类新型离子通道阻滞剂用于治疗自身免疫性疾病

• 批准号: 10053003
• 金额: $ 248.26万
• 依托单位: MAXION THERAPEUTICS LIMITED
• 依托单位国家: 英国
• 项目类别: Collaborative R&D
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=10053003
• 关键词: Development; novel; class; ion; channel

Autoimmune diseases such as Inflammatory Bowel Disease, Type 1 Diabetes, Rheumatoid Arthritis and Psoriasis are driven by the protective immune system attacking the body itself. These conditions are often poorly treated with existing therapeutics. Autoimmune diseases are driven by a subset of T cells (part of the body's immune system) which are uniquely dependent on an ion channel called Kv1.3\. Blockade of the action of Kv1.3 therefore provides an "Achilles heel" to precisely disable this subset of autoimmunity-driving T cells while leaving the rest of the immune system intact to continue fighting infections.Creating an antibody drug to block Kv1.3 is an attractive option. Antibody drugs have ideal properties for disease intervention and over 100 different antibody drugs have been approved in the last 20 years. Making antibodies which block ion channels, however, remains a challenge despite decades of effort.Nature provides the answer in the form of "miniproteins" (knottins) which are found in venoms and which block ion channels. This includes a knottin present in the venom of a sea anemone that blocks Kv1.3\. Unlike antibodies, knottins suffer from problems such as rapid removal from the blood circulation and unwanted cross-reactivity in the body causing side-effects.By fusing a Kv1.3-blocking knottin directly into the surface of an antibody, Maxion has created a "hybrid molecule" (a "KnotBody") which combines the best of both worlds. The resulting molecule has the optimal characteristics of an antibody AND blocks Kv1.3\.Within this project Maxion will use powerful antibody engineering tools, invented by Maxion's founder Dr. John McCafferty, to improve the potency of the initial KnotBody and progress the resulting drug candidate towards clinical trial. Ultimately Maxion aim to develop a KnotBody drug which will significantly improve the quality of life of patients by preventing conditions such as Inflammatory Bowel Disease, Type 1 Diabetes and Atopic Dermatitis.

自身免疫性疾病，如炎症性肠病、1型糖尿病、类风湿性关节炎和牛皮癣，都是由攻击身体的保护性免疫系统驱动的。这些情况通常用现有的治疗方法治疗得不好。自身免疫性疾病是由T细胞(人体免疫系统的一部分)的子集驱动的，这些T细胞唯一地依赖于一种称为Kv1.3的离子通道。因此，阻断Kv1.3的作用提供了一个“阿喀琉斯之踵”，可以精确地使这一自体免疫驱动的T细胞亚群失效，同时保持免疫系统的其余部分完好无损，以继续对抗感染。创造一种抗体药物来阻断Kv1.3是一个有吸引力的选择。抗体药物具有理想的疾病干预性能，在过去的20年里已经批准了100多种不同的抗体药物。然而，尽管经过数十年的努力，制造阻断离子通道的抗体仍然是一个挑战。大自然以“小蛋白”(结蛋白)的形式提供了答案，这种蛋白存在于毒液中，可以阻断离子通道。这包括海葵毒液中存在的一种结蛋白，它可以阻止Kv1.3。与抗体不同，结蛋白存在快速从血液循环中移除和体内不必要的交叉反应等问题，导致副作用。通过将阻断Kv1.3的结蛋白直接融合到抗体表面，Maxion创造了一种结合了这两个世界最好的“杂交分子”(“结体”)。在这个项目中，Maxion将使用由Maxion创始人John McCafferty博士发明的强大的抗体工程工具来提高初始结体的效力，并将得到的候选药物进行临床试验。Maxion的最终目标是开发一种结体药物，通过预防炎症性肠病、1型糖尿病和特应性皮炎等疾病，显著提高患者的生活质量。