GOALI: Collaborative Research: Structure, Stability, and Mechanisms of Nonnative Protein Aggregate & Microparticle Formation

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0931173/0932155Roberts/FernandezIntellectual merit This project seeks to lay a foundation to fill key gaps in mechanistic understanding of the formation of nonnative microparticles vs. soluble aggregates, the thermodynamics of aggregate-particle phase separation, and key interactions that stabilize aggregates / particles and control their morphology. The model protein systems are alpha-chymotrypsinogen A (aCgn) and the Fc region of human immunoglobulin gamma-1 (IgG1-Fc). aCgn is a well-studied starting point, based on its established mechanisms of soluble aggregate formation, and its empirical ability to form both aggregates and microparticles. IgG1-Fc is a useful bridge to commercially viable proteins, as it is a key domain in a range of biopharmaceutical proteins that are based on either monoclonal antibodies (MAbs) or fusion constructs, and preliminary data also indicates it readily forms both soluble aggregates and particles.Broader impactsThe project addresses a long-standing and potentially very high impact problem in the biopharmaceutical industry. The proposed research will result in an improved mechanistic understanding of aggregation and particle formation; thereby providing a basis for future efforts in the PI's laboratories and those of others to rationally design and control aggregation resistance, as well as for control of aggregate and particle structure / morphology across major classes of biotechnology products such as MAbs and antibody-fusion proteins. The collaborative research plan involves significant student mentoring and scientific contributions from the co-PI from Amgen, including extended student internships and regular team meetings. Through these collaborations, including work in the academic institutions, this project will provide a framework for the education and training of graduate and undergraduate students in the PIs' laboratories, with a specific focus on cutting-edge experimental and modeling tools. As in the past, the PIs at UVA and UD will involve students drawn from underrepresented groups in science and engineering. Finally, a set of examples and problems will be developed to incorporate aspects of this research into the undergraduate curricula, including computational and modeling activities. These modules will be disseminated to other faculty via a web-based repository of educational materials led by San Jose State University that was co-developed by one PI at Virginia.