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

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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.