Optimization of Protein Therapeutics Formulations

DESCRIPTION (provided by applicant): This proposal involves the development of a high-throughput self-interaction chromatography (SIC) system that will be used by Soluble Therapeutics, LLC, to improve and accelerate the formulation discovery process for biopharmaceuticals (i.e. vaccines, monoclonal antibodies and other therapeutic proteins). Biopharmaceuticals are used to treat a variety of infectious and chronic diseases. According to a Data-Monitor Report published in June, 2008, protein therapeutics represents the second largest segment in pharmaceutical drug discovery. Since 2000, more than 25% of all new drugs approved have been biopharmaceuticals but there development is a time-consuming and costly endeavor. The development of biopharmaceuticals requires that the protein therapeutic is highly soluble since a substantial amount of the protein must be injected in patients via a small volume of solution. Pharmaceutical and biotechnology companies devote significant time and resources developing suitable formulations that allow the desired protein to be concentrated to high levels without inducing instability in the protein. This process of formulation development is often the major bottleneck in the protein therapeutic discovery process. The HSC technologyprovides a new paradigm for rapidly improving the solubility and physical stability of biopharmaceuticals. The paradigm was validated in phase-1 studies using vaccine candidates obtained from two pharmaceutical companies as well as the proteins osteoprotegerin (involved in bone mineralization and osteoporosis), the cystic fibrosis transmembrane conductance regulator protein (CFTR), the nucleotide-binding domain-1 of CFTR and phospholipase-D1 (a human enzyme responsible for the hydrolysis of phosphatidyl choline). A prototype 2nd generation system was used to improve the solubility and physical stability of each protein by measuring the second virial coefficient (B-value) for the protein in solutions containing different excipients. In addition to developingthe 3rd generation system, a second area with significant commercial potential will simultaneously be validated. This involves use of SIC to optimize stabilization of protein complexes and to screen compound or peptide libraries for those that inhibit oraugment protein-protein interactions. The development of a 3rd generation, higher throughput system is needed to meet the market demand demonstrated by Soluble Therapeutics via meetings with pharmaceutical and biotechnology company representatives. The proposed technology will accelerate and improve development of clinically useful biopharmaceutical formulations, research conducted by pharmaceutical, biotechnology, government and academic communities. It will also benefit any protein expression research organization (expressing aqueous or membrane proteins) that desires improved solubility and physical stability of expressed protein. It will reduce the cost and time required to develop new vaccines, monoclonal antibodies and other protein therapeutics. Soluble Therapeutics, LLC intends to support biopharmaceutical research as a CRO by establishing collaborative relationships with researchers from industry, academia and the government. PUBLIC HEALTH RELEVANCE: Protein drugs such as insulin, vaccines andantibody therapies interact with natural biomolecular processes in the human body to prevent and treat disease. A significant number of protein drugs - although identified to be relevant to a disease state - are unable to be taken to market by pharmaceutical companies due to the difficult challenge of identifying a formulation which makes the protein drug physically stable and soluble at high concentration. The proposed research will enable Soluble Therapeutics to more rapidly (and cost effectively) to bring new protein drugs to patients.