α-1 antitrypsin (AAT) is used as augmentation therapy in patients with AAT deficiency (AATD)-related emphysema, and is a promising therapeutic for treatment of a wide range of inflammation and autoimmune diseases. However, patients undergoing weekly infusions of AAT augmentation therapy exhibit declining levels of circulating AAT, due to its propensity to aggregate and inactivate, thus requiring extremely high weekly doses (60 mg/Kg of bodyweight). Current AAT augmentation utilizes wildtype, heterogeneous plasma-purified AAT, which is not optimized for this purpose. In this talk I will describe how we are using protein engineering to produce novel AAT variants with enhanced activity and durability, offering a route to pre-clinical candidates with superior therapeutic potential.
I completed my PhD in 1994 in the laboratory of Prof Sir Alan Fersht at the University of Cambridge, on the structure determination of protein-DNA and protein-protein complexes. As a postdoc then staff scientist at the MRC Centre Cambridge, I made contributions to the understanding of protein stability, molecular recognition and the action of molecular chaperones. I relocated to Monash University, Australia in 2003 and am currently a group leader in the Department of Biochemistry and Molecular Biology.