Screening of Antibodies as Tresk Channel Activators for Pain Management
Abstract
This project responds to the Topic Area "Non-Opioid Pain Management." It directly addresses the Area of Encouragement "Development of non-opioid pain medicine to provide adequate relief of pain." Our objective is to use two parallel approaches to screen for antibodies that can specifically bind to the human potassium channel TRESK and enhance channel activity. We envision that TRESK-enhancing antibody will have long-lasting effects on reducing many types of chronic pain. Since the antibody works through silencing pain-sensing neurons outside the brain, it will not compromise patients cognition, judgement, cardiovascular, and respiratory functions. Neither will it lead to drug overuse/abuse problems as opioid drugs. Chronic pain affects over 100 million Americans, more people than cancer, heart disease, and diabetes combined. Nearly half of wounded Soldiers and Veterans in the Iraq and Afghanistan conflicts suffer from chronic pain that adversely affect their return to active duty or a fully functional civilian life. Although the number of prescriptions for pain medications has skyrocketed during the last 10 years, chronic pain remains inadequately treated. While opioids are, by far, the most effective pain relievers, opioid-related respiratory depression, addiction, dependence, and overdose are more prevalent than ever. Opioid overdose now kills more people than cocaine or heroin. There is an urgent need for new pain medicine with fewer side effects and lower risk for overdose/abuse. TWIK-related spinal cord potassium (TRESK) channel mediates the outflow of potassium ions from pain-sensing neurons, making them less responsive to painful stimuli. Previous studies suggest that enhancing the activity of TRESK channel can produce pain relief with minimal side effects. Unfortunately, attempts to develop small molecule drugs that specifically enhance TRESK activity have not been successful to date. We reason that, compared with small molecules, antibody drugs may be better treatments for chronic pain, as antibodies have longer-lasting effects, fewer off-target side effects, and fewer adverse effects on brain function. In this study, we propose a novel strategy to screen for antibodies as TRESK channel activators. This is highly innovative, as the prospect of antibodies as channel activators has not been explored. We will employ two parallel approaches to ensure the thoroughness of antibody screening. With the first approach, we will screen a library that contains 1x1010 combinations of human antibodies to enrich antibodies that specifically bind to human TRESK channels (the binders). We will then use a high-throughput assay to identify the binders that enhance TRESK channel activity (the activator). We will randomly alter the sequence of the activators to increase their potency and/or efficacy. With the second approach, we will immunize mice with cells expressing human TRESK channels and use mice that produce a high level of TRESK antibodies to generate large numbers of hybridoma cell lines. We will screen these lines for hybridoma-derived antibodies that specifically bind to human TRESK and enhance channel activity. We anticipate that we will identify several monoclonal antibodies as TRESK-specific enhancers upon completion of the project. They can be further humanized and produced for a Phase I clinical trial as novel pain medicine in the near future. We envision that many types of chronic pain will be effectively treated by the TRESK-enhancing antibodies. We predict that patients will experience long-lasting pain relief with minimal side effects on brain and cardiovascular functions. This will benefit millions of Soldiers, Veterans, as well as civilians that suffer from chronic pain, improving their quality of life and reducing the risks of substance abuse.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710106
Entities
People
- Yuqing Cao
Organizations
- United States Army
- Washington University in St. Louis