Preferred binding regions for highly selective and orthogonal multimodal protein separations

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The development of protein-based medicines is having an increasing impact on treatment of many diseases such as cancer, diabetes, and multiple sclerosis. Example protein-based therapeutics for these diseases include rituxan, insulin, and avonex, respectively, with many more in various stages of discovery and development. However, the costs of producing these drugs and the challenge of obtaining highly pure drugs with minimal side effects is a major challenge. Often, negative side effects are due to small amounts of impurities that are extremely similar to the desired medicine and thus very difficult to remove. This NSF funded project will develop new methods for efficiently removing these challenging drug impurities from a range of biopharmaceuticals, resulting in reduced production costs, safer medicines and more patient access.This experimental and computational project will focus on the development of multimodal ligands for chromatographic resins, which will be used to achieve highly selective separations of complex biological products. The new multimodal ligands will increase selectivity by targeting specific regions on protein surfaces, enabling the effective removal of bioproduct related impurities, a critical challenge in biomanufacturing. Experimental characterization techniques will validate molecular-level binding information. The computational work will predict key binding faces and relative binding affinities and will produce powerful predictive tools for bioprocess development. The development of multimodal systems with unique and targeted selectivities on specific protein surface regions will enable the development of highly effective orthogonal downstream processes guided by molecular level understanding and predictive tools. This will result in reduced costs and improved product quality and safety. Graduate and undergraduate students working on this project will be directly exposed to the state of the art in biophysics, chromatography and molecular simulations. More broadly, the concepts will be incorporated into both undergraduate coursework and on-line animated movies for the the Molecularium project, the flagship outreach and education effort of Rensselaer Polytechnic Institute's Nanotechnology Center.