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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的 T 细胞介导的自身免疫性疾病和慢性炎症疾病影响着 2300 万美国人，相当于每年约 100B 美元的直接医疗费用。制药技术的进步使得开发针对这些疾病的治疗方法，但现有药物具有严重的免疫- 副作用较小，因为它们广泛针对所有 T 细胞活性。电压门控离子通道 Kv1.3 是经过验证的自身免疫性疾病治疗靶点。 Kv1.3是有差别的在疾病相关 T 细胞类型（激活的效应记忆 TEM 细胞）上表达，使其成为更具选择性（且更安全）的目标。针对 Kv1.3 的小分子和肽类药物在几乎所有人类离体和自身免疫性疾病大鼠模型中均显示出功效人体临床试验。然而，现有的分子显示出较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，例如单克隆抗体，预计在治疗自身免疫性疾病方面非常有效，且副作用较少。然而，针对 Kv1.3 等离子通道的抑制性单克隆抗体对于隔离，因为离子通道形成复杂的跨膜结构，当过度时是有毒的表达，并且很难从其天然脂质环境中纯化出来。在这里我们建议开发 Kv1.3 单克隆抗体来治疗自身免疫性疾病和慢性炎症性疾病。