Research Project
8000889
DESCRIPTION (provided by applicant): Antigen-microarray validated monoclonal antibody library for analysis of brain- expressed proteins implicated in human mental disorders. Summary This is a proposal to produce a targeted set of monoclonal antibodies to be commercialized in a variety of ways (see commercialization plan), briefly summarized here as Research (short term), Diagnostics (middle term) and Therapeutics (long term) as a collaborative effort by a startup company in Mayaguez, Puerto Rico, CDI, and the High Throughput Biology Center (HiT) at Johns Hopkins University. The company has developed an efficient pipeline to produce monoclonal antibodies using a complete collection of antigen clones provided by HiT. An antigen array-based protein validation technology developed by the HiT Team forms a critical component of a validation pipeline that allows CDI to rapidly identify antibodies against important and valuable antigens and of very high specificity. The great majority all human genes are expressed in the brain, with many thousands of transcripts expressed in highly cell, region and developmental stage-specific patterns, and recent years have identified many genes as being implicated in the pathology of mental illness. Thus it is critical to have a high-quality set of protein affinity tools to measure, map, and visualize all of these components. Antibodies are the workhorses of protein research because of their use in immunohistochemistry, (co)immunoprecipitation, ChIP on chip, immunoblotting and many other methods. Antibodies vary dramatically, however, in quality;the most commonly used antibodies are polyclonal and thus suffer from significant batch-to-batch variation. Whereas many protein affinity reagents have been described, none has the robust sensitivity and specificity performance of conventional, two-chain antibodies and we focus on streamlining this very well developed technology. We will develop a systematic technology to isolate ultra high specificity renewable monoclonal antibodies, based on exploiting novel antigen microarrays in combination with high throughput production approaches we have developed. Because CDI is located in Puerto Rico, it will be possible to produce large numbers and quantities of mAbs efficiently due to the lower labor costs offshore, while providing excellent training and job opportunities on the island. Our goal in this Phase I application is to produce at least 60 high-grade monoclonal antibodies to transcription factors implicated in human brain development and mental illness. If this approach proves successful, we will expand our effort to produce antibodies to several hundred additional human proteins that are implicated in brain development and/or mental illness in Phase II. PUBLIC HEALTH RELEVANCE: Specific antibodies (or the lack there of) has been a major issue for every colleague we know who has worked in the field of molecular psychiatry. It is a common experience to see an antibody in a catalog advertised as having certain properties or specificity and then finding it to be effectively useless. If the science of molecular psychiatry is to mature, then a series of well validated, reproducible protein affinity reagents is essential. We have developed an approach to rapidly validate antibody specificity. We propose to use this tool to generate a large set of monoclonal antibodies of verified specificity that selectively react with human proteins that are involved in mental illness or brain development. This resource will directly benefit both the mental health research community and the larger biomedical community.
