Bioprocessing of Plasma Therapeutic Proteins using Sequential Affinity Monolithic

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Department of Health and Human Services
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Phase I
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(401) 301-2046
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DESCRIPTION (provided by applicant): Plasma fractionation is one of the largest industry segments in global therapeutic protein manufacture. The United States plays an important role in this industry since it represents the largest plasma collection and ma nufacturing base that accounts for more than 50% of the world supply of plasma. Even though more than 22 million liters of plasma are collected each year for fractionation, this amount cannot meet the high demand for plasma derivatives worldwide such as al bumin (about 500 tons), FVIII (2 kg) and IgG (40 tons). Consequently, optimal fractionation methods are important to increase the various therapeutic proteins extracted from plasma and to improve the yields of the purified products. In spite of the continu ed prevalence of protein based blood products in the clinical arena, the methods currently used to obtain them known as fractionation, are outdated and inefficient, a case in point being ethanol fractionation, a purification process developed during World War II that still remains the backbone of most fractionation strategies in use today The recent addition of chromatographic methods for industrial scale plasma fractionation has become a standard approach in the last few years that has played a central rol e in the development of a new generation of highly purified therapeutic plasma derivatives that includes coagulation factors, protease inhibitors and anticoagulants. Nevertheless, the scarcity of human plasma has created a pressing need for improving the y ield of purified plasma proteins obtained using current fractionation technologies. The FDA through the Center of Biologics Evaluation (CDER) has long recognized that the development of biological products is becoming increasingly challenging. The agency h as suggested that superior product development sciences are needed to address the challenges of greater efficiency and lower costs, essential goals if the United States is going to remain a leader in the develop of plasma derived therapeutics. In recogniti on of this need, in this proposal, we will develop a strategy to radically improve the bioprocessing of plasma derived protein therapeutics by using specific affinity ligands immobilized on a new generation of chromatographic supports, an approach that sho uld increase the yield, speed of production and quality of plasma derived products. Specifically, we will make use of Convective Interaction Media (CIM), a recently developed revolutionary chromatographic support based on methacrylate monoliths. In the pro posed studies, a sequential chromatographic separation of human plasma on several affinity CIM supports will be designed to streamline the fractionation process of existing plasma derivatives such as immunoglobulins and clotting factors but also of newer c lasses of plasma derived products such as protease inhibitors. In Specific Aim 1, we will develop affinity supports specific for various plasma proteins by immobilizing antibodies, peptides or synthetic dyes on epoxy-activated CIM columns. A major goal wil l be to optimize the immobilization conditions by assessing performance, stability, and reusability of ligands coupled under different conditions and densities. In Specific Aim 2, we will develop purification protocols based on serially linked-affinity CIM discs with the goal of obtaining a high level of purity and activity in a single step purification. We will also evaluate the yield and purity following scale-up of CIM separation protocols, a necessary step towards industrial level production that will b e facilitated by the identical performance and purification profiles of short monoliths independently from their size or shape (disk, column or tube), The results of these investigations should provide the proof of concept for the use of CIM technology i n industrial fractionation of human plasma.

* information listed above is at the time of submission.

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