Development of Kv1.3 Monoclonal Antibodies Targeting TEM Cells for Treating Autoimmune Disorders

摘要 T细胞介导的自身免疫和慢性炎症性疾病影响着2300万美国人， 相当于每年约1,000亿美元的直接医疗成本。制药方面的进步使 这些疾病的治疗方法的发展，但现有的药物具有严重的免疫力- 因为它们广泛地针对所有的T细胞活动，所以具有妥协的副作用。电压门控离子 Channel Kv1.3是自身免疫性疾病的有效治疗靶点。Kv1.3是不同的 表达在与疾病相关的T细胞类型(激活的效应记忆TEM细胞)上，使其成为一种 更有选择性(也更安全)的目标。抗Kv1.3的小分子和多肽类药物 在几乎所有人类体外和自身免疫性疾病的大鼠模型中都显示出有效性，以及 人体临床试验。然而，现有的分子表现出较差的药代动力学和交叉。 与其他Kv家族成员的反应性。可以克服这些问题的药物，如单抗， 预计在治疗自身免疫性疾病方面非常有效，副作用较少。 然而，针对离子通道的抑制性单抗，如Kv1.3，对 分离是因为离子通道形成复杂的跨膜结构，当过量时是有毒的 表达，并且很难从天然的脂类环境中提纯。在这里，我们建议 开发用于治疗自身免疫性和慢性炎症性疾病的Kv1.3单抗。

ABSTRACT T cell-mediated autoimmune and chronic inflammatory diseases affect 23 million Americans, corresponding to ~$100B/year in direct healthcare costs. Pharmaceutical advances have enabled the development of treatments for these diseases, but existing drugs have severe immune- compromising side effects because they broadly target all T cell activity. The voltage-gated ion channel Kv1.3 is a validated therapeutic target for autoimmune diseases. Kv1.3 is differentially expressed on disease-relevant T cell types (activated effector memory TEM cells), making it a more selective (and safer) target. Small molecule and peptide-based drugs against Kv1.3 have shown efficacy in nearly every human ex vivo and rat model of autoimmune disease, as well as human clinical trials. However, existing molecules show poor pharmacokinetics and cross- reactivity with other Kv family members. Drugs that can overcome these issues, such as MAbs, are predicted to be highly effective in treating autoimmune disorders with fewer side effects. However, inhibitory MAbs against ion channels such as Kv1.3 are extremely challenging to isolate because ion channels form complex transmembrane structures, are toxic when over- expressed, and are difficult to purify away from their native lipid environment. Here we propose to develop Kv1.3 MAbs to treat autoimmune and chronic inflammatory disorders.