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

开发针对 TEM 细胞的 Kv1.3 单克隆抗体用于治疗自身免疫性疾病

• 批准号: 10374043
• 负责人: JOSEPH Benjamin RUCKER
• 金额: $ 58.95万
• 依托单位: INTEGRAL MOLECULAR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374043
• 关键词: Abbreviations; Address; Affect; Affinity; American; Animal Model; Antibodies; Autoimmune; Autoimmune Diseases; Binding; Biological Assay; Biological Markers; Biosensor; Cardiac; Cell Line; Cells; Chronic; Clinical; Clinical Treatment; Clinical Trials; Complex; Data; Delayed Hypersensitivity; Development; Disease; Drug Kinetics; Drug or chemical Tissue Distribution; Effector Cell; Electrophysiology (science); Engineering; Environment; Epitopes; Experimental Autoimmune Encephalomyelitis; Family member; Formulation; Future; Goals; Health Care Costs; Human; Immune; Inflammatory; Interferon Type II; Interleukin-2; Ion Channel; Ion Channel Gating; Kinetics; Lead; Lipids; Lupus; Maps; Mediating; Membrane; Membrane Potentials; Memory; Modeling; Monoclonal Antibodies; Mutagenesis; Neurons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Probability; Proteins; Proteome; Psoriasis; Psoriatic Arthritis; Public Health; Rattus; Research; Rheumatoid Arthritis; Risk; Safety; Sales; Shotguns; Small Business Innovation Research Grant; Specificity; Structure; T memory cell; T-Lymphocyte; Technology; Testing; Therapeutic Monoclonal Antibodies; TimeLine; antibody engineering; biopharmaceutical industry; blood-brain barrier crossing; candidate selection; cell type; chronic inflammatory disease; cross reactivity; differential expression; efficacy testing; graft vs host disease; human disease; immunogenicity; improved; in vivo; inhibitor; lead candidate; overexpression; peptide drug; phase 1 study; phase 2 study; preclinical study; side effect; small molecule; subcutaneous; success; terminally differentiated effector memory (TEM) T cells; therapeutic development; therapeutic target; therapy development; voltage

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.

摘要 T细胞介导的自身免疫性和慢性炎症性疾病影响着2300万美国人， 相当于每年约1000亿美元的直接医疗保健成本。制药技术的进步 这些疾病的治疗方法的发展，但现有的药物有严重的免疫- 因为它们广泛靶向所有T细胞活性。电压门控离子 通道Kv1.3是自身免疫性疾病的有效治疗靶点。Kv1.3是不同的 在疾病相关的T细胞类型（激活的效应记忆TEM细胞）上表达，使其成为 选择性更强（也更安全）的目标。针对Kv1.3的小分子和肽类药物 在几乎每一种人离体和大鼠自身免疫性疾病模型中显示出有效性， 人体临床试验。然而，现有的分子显示出差的药代动力学和交叉- 与其他Kv家族成员的反应。可以克服这些问题的药物，如单克隆抗体， 被预测在治疗自身免疫性疾病方面非常有效，副作用更少。 然而，针对诸如Kv1.3的离子通道的抑制性MAb对于 隔离是因为离子通道形成复杂跨膜结构，当过度时是有毒的， 表达，并且难以从其天然脂质环境中纯化。在这里我们建议 开发Kv1.3单克隆抗体以治疗自身免疫性和慢性炎症性疾病。