Tuesday, 2nd December, 2014, 12.00-13.00

Rational design of antibodies targeting intrinsically disordered proteins

In biological systems nearly all processes are governed by interactions between protein molecules, which have evolved to perform an innumerable variety of functions. The ability of some proteins, such as antibodies, to interact with high affinity and specificity is being increasingly exploited for therapeutic and diagnostic applications. Yet, using current methods it is laborious and often difficult to generate antibodies against specific epitopes within a protein, in particular within disordered regions. Likewise, the successful development of antibody-based drugs is often hindered by their relatively poor solubility, which leads to aggregation at the high concentrations necessary for effective storage and delivery. 
I will present two computational approaches to rationally modify interactions between protein molecules, including antibodies. The aim of the first is to hamper aberrant interactions by predicting mutations that improve the solubility, while retaining native state and activity. Its application to a single-domain antibody demonstrates that solubility changes upon mutation are estimated with great accuracy, thus offering a cost-effective strategy for the production of soluble proteins. The second consists in the rational design of protein-protein interactions by engineering a scaffold to bind to virtually any target disordered epitope in a protein. We validate this method by designing five single domain antibodies to bind different epitopes within three disease-related intrinsically disordered proteins (α-synculein, Aβ and IAPP). The results show that all antibodies bind to their target with good affinity and specificity. As an example of an application we carried out further experiments on one of these antibodies to show that it inhibits the aggregation of α-synuclein at low substoichiometric concentrations, and that binding indeed occurs at the selected epitope.

Speaker: Pietro Sormanni, PhD Student, Department of Chemistry, University of Cambridge, Cambridge

Room Aula room (470.03 – 4th floor)