GOALI: Collaborative Proposal: Mechanistic Design of Aggregation Resistance in Multi-Domain Proteins

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Roberts/Robinson1264329/1264554 Non-native aggregation denotes a set of molecular processes by which a folded, biologically active protein becomes effectively locked into a ?misfolded? assembly or aggregate of proteins. Formation of these aggregates is a ubiquitous hurdle to successful over-expression, purification, and storage of recombinant proteins throughout the biotechnology and biopharmaceutical industries. This is particularly the case for multi-domain proteins, such as natural and designed antibodies, as well as for other predominantly-beta proteins. Predictive design of these more complex proteins is handicapped by limitations in the mechanistic understanding of key features of sequence and structure that control aggregation of multi-domain proteins. This project seeks to improve fundamental understanding of the mechanism(s) of multi-domain protein aggregation, so as to provide general design rules to engineer aggregation resistance into therapeutic proteins and other biotechnology products. This is a partnership between Amgen, Tulane University, and the University of Delaware through the National Science Foundation?s industry-university GOALI program. The work will focus on computational design of new antibody molecules that retain their known function (e.g., ligand binding) while greatly reducing their aggregation rates, and then experimentally characterizing the aggregation pathways to assure that the design predictions worked properly at a molecular level. From a broader perspective, the project focuses on creating new experimental and computational tools to better predict and control or even eliminate aggregates in protein pharmaceuticals and other biotechnology products. Doing so will decrease the cost of development for industrial scientists and engineers, and also decrease the time to market and any safety risks associated with protein aggregates in medical applications. The biopharmaceutical industry is one the fastest growing and attractive industries for growth of the U.S. job market requiring a highly trained workforce that will maintain international competitiveness. An indirect but equally important outcome of this project is the training of the next generation of industrial scientists and potential leaders for the industry, as well as development of new educational tools for more broad use throughout the technical community, and potentially for direct use in demonstrations in high school science courses such as chemistry, biochemistry, biology, and physics.