Discovery of KCa3.1-Inhibiting Antibodies for the Treatment of Asthma
Abstract
Topic Areas: (1) Asthma and (2) Pulmonary Fibrosis Asthma is a chronic disease associated with inflammation and spasms of the airways in the lungs. It is estimated that 26 million people suffer from asthma in the United States, and recent decades have shown a concerning increase in the prevalence of asthma in both children and adults. The costs related to asthma have also been steeply increasing, from ~$12 billion in 1994 to ~$56 billion in 2011. It has also been shown that the frequency of development of asthma is considerably higher in U.S. Service personnel compared to the civilian population. For Soldiers that have been deployed to Iraq and Afghanistan, it is thought that exposure to fine sand particles, irritants, and toxins related to burning trash in “burn pits” may be the cause. Currently, asthma cannot be cured and treatment guidelines emphasize the use of preventive anti-inflammatory drugs (e.g., inhaled corticosteroids) to control the disease symptoms. Treatment with corticosteroids helps to manage the disease for a majority of patients, but for unknown reasons approximately 10% of patients are resistant to broadly immunosuppressive drugs. This project proposes to discover a new class of drugs, monoclonal antibodies, for the treatment of asthma. A significant advantage of developing therapeutic antibodies is that they are typically much more selective in their mode of action, associated with fewer side effects and are therefore safer. A growing body of evidence implicates a human protein called KCa3.1 in the pathogenesis of asthma. The development of antibodies that target and alter the function of proteins like KCa3.1 has long been recognized by pharmaceutical scientists as a prized alternative for the treatment of variety of diseases. Historically, however, this has been very challenging primarily due to the lack of a robust source of target protein that will support an antibody drug discovery program. This bottleneck has been solved recently by a technology that uses Tetrahymena thermophila, a single cell organism, for the production of these proteins in quantities that are hundreds of fold greater than has previously been possible. This proposal aims to produce large quantities of KCa3.1 and formulate it for animal immunizations for the production of anti-KCa3.1 antibodies. The antibodies will be screened for those that can inhibit the function of KCa3.1. Follow-on studies will endeavor to develop identified inhibiting antibodies as therapeutic candidates for the treatment of asthma. In addition to its role in asthma, there is strong evidence that KCa3.1 is involved in the progression of other diseases related to inflammation. If successful, the antibodies identified during the course of achieving the aims of this proposal can potentially be developed for the treatment of other diseases identified by the Department of Defense as high priority. These include inflammatory bowel disease as well as pulmonary fibrosis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810030
Entities
People
- Ashot Papoyan
Organizations
- TetraGenetics (United States)
- United States Army