Ion channels, such as Kv1.3 and Nav1.7, are involved in a number of human disorders, including autoimmunity and pain that affect >100 million Americans annually and are poorly treated. However, ion channels are typically exceptionally difficult to express at high levels due to their structural complexity and toxicity. s a result, many research and therapeutic applications for these targets have been very limited where high-levels of membrane protein are required. For example, for human voltage-gated potassium (Kv) and sodium (Nav) ion channels, there are no solved crystal structures and no therapeutic monoclonal antibodies (MAbs) approved by the FDA or even in clinical trials, despite the high level of pharmaceutical interest in such MAbs as therapeutics. These applications all typically require high levels of protein expression, and the expression of most ion channels is usually orders of magnitude below what is required for success. Here we propose to develop a versatile platform for expressing high levels of conformational ion channel proteins. Our use of this platform within the scope of this proposal will be for isolating unique MAbs against Kv1.3 and Nav1.7. We expect that this platform will be extensible to other ion channels and will also have utility for structural research, high-throughput screening, and as biomedical research reagents.
This proposal will contribute to human health and the cure of human disease through the development of a platform for high-expressing ion channels that can be used for research and therapeutic applications. Our own use of this platform within the scope of this proposal will be for isolating unique MAbs that can be developed into human therapeutics to treat pain and auto- immune disorders, conditions that affect >100 million Americans each year and that currently have poor treatments. We expect that this platform will also have utility for structural research, high-throughput screening, and as biomedical research reagents.