Tuesday, May 6, 2025
5/6/2025
High Content Screening for Bifunctional Chimera Biologics - SUMMARY High content screening is one of most of the important advances in drug discovery. It has enabled automated high-throughput discovery of many small-molecule drugs to treat human disease. However, recent decades have seen the development of over 400 Biologic drugs based on proteins, rather than chemical entities. Examples include insulin, erythropoietin, growth-factor inhibitors, and monoclonal antibodies, which improve the Quality of Life and lifespan of millions of patients. Despite this impact, there is no high content technology to screen cellular functions to create and assay new Biologic drugs. Heligenics has developed the “GigaAssay” to characterize the activity of vast libraries of protein variants. In previous studies of our SBIR projects, a specific GigaAssay was created to identify soluble variants of Interferon, a family of proteins involved in immunity and auto-immunity, which are used to treat Multiple Sclerosis. In this Direct Phase II proposal, we will extend the GigaAssay approach to create and screen libraries of bifunctional Interferon chimeras for improved cell stimulatory function. Bifunctional proteins have been recently developed as advanced treatments for cancer, obesity, and diabetes, and many others are in clinical trials. These drugs are safer and more efficacious than their mono-functional predecessors. Many methods are available to create libraries of protein variants, but no platform exists for high-throughput functional screening of libraries of protein families or chimeric Biologics. The GigaAssay developed in previous studies allowed Heligenics to both generate and measure the function of all possible single-residue substitutions or 1,000’s of chimeras at once. In Aim 1 of our Direct Phase II proposal, we will evaluate a library of over 50,000 bi-functional Interferon chimeras to isolate and test a more active protein product. In Aim 2, the most effective chimeras will be confirmed in cell-based assays. In Aim 3, biological properties and disease-modifying activity of the leads will be compared to FDA-approved Interferon drugs in a mouse model of Multiple Sclerosis. Heligenics intends to develop the Interferon chimera leads and advance them to clinical trials with a major pharmaceutical partner. Validation of the GigaAssay for high content screening in this SBIR Direct Phase II project will establish this approach as a unique and powerful means to identify new bi-functional protein chimeras for drug development.
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