Improving antibody drug delivery to the brain via surface sugars
Erskine visitor from the University of Washington, Tacoma
Time & Place
Wed, 14 Aug 2019 12:00:00 NZST in Room 701, West
All are welcome
Currently, no drug slows the progression of Alzheimer’s Disease. A major limitation of existing Alzheimer’s drug candidates is poor penetration through the blood-brain barrier. While therapeutic antibodies may offer a viable Alzheimer’s treatment strategy, less than 1% of such antibody infusions actually reach the central nervous system. To improve antibody pharmacokinetics in favour of brain penetration, antibody glycan sialylation was investigated as a means to alter permeability through the blood-brain barrier (BBB). Fab glycan sialic acid was found to inhibit efflux of monoclonal antibody 4G8 out of the brain while influx remained unaffected. By contrast, sialylation of polyclonal human IgG antibodies slowed both influx and efflux. Glycan profiling of 4G8 and human IgG reveals a number of notable differences in the extent of Fc sialic acid, glycolated sialic acid, and a-Gal groups. Such differences may explain the variable blood-brain barrier permeability of these two preparations. In short, efflux inhibition via sialylation can significantly increase antibody drug delivery. Furthermore, glycan sialylation is compatible with other methods that increase antibody influx into the brain. In addition to improving future Alzheimer’s drugs, sialylation may enable previously failed drugs a second chance to succeed.
My research at the University of Washington focuses on improving the delivery and retention of drugs into the brain. Specifically, my lab exploring how changes in surface carbohydrates on antibody drugs can increase their influx into the brain and reduce their efflux out of the brain so that overall delivery is elevated. My group currently works with antibody drugs used to treat both Alzheimer’s Disease and breast cancer. Brain delivery remains a major hurdle to effective treatment of most central nervous system disorders and our work aims to reduce this crucial barrier. I have a B.A. in Bio-chemistry from Claremont-McKenna College, M.S. and Ph.D. in Chemistry from the University of California San Diego, and completed a post-doc in Physics at the University of California San Diego. I worked as an Assistant Professor at Oakland University prior to my current position of Associate Professor at the University of Washington. In addition to my research, I have also led an effort to expand an urban University of Washington campus in the city of Tacoma (UW Tacoma). In this regard, I have helped create a new Biomedical Sciences B.S. program that serves local students that are first generation, place-bound, and/ or from underrepresented backgrounds in science. As such, I understand many of the struggles today’s students face as they pursue their education and I hope to bring this perspective into my teaching here at the University of Canterbury. I’ll be helping out with teaching and lab sections in BCHM281, CHEM339, and BCHM/CHEM443.