(230f) Predictive Tools for Protein Aggregation

Aggregation is a major degradation pathway for therapeutic proteins such as antibodies during their storage at high concentrations for various applications including chronic inflammatory diseases and cancer.  Aggregation leads to a decrease in protein activity and raises concerns about an immunological response.  Here we describe a new approach to design therapeutic proteins with decreased aggregation propensity using molecular computational and genetic engineering techniques.^1,2   Using full antibody atomistic molecular dynamics simulations, we identify the protein regions prone to aggregation by using a tool that we developed called 'spatial-aggregation-propensity (SAP)'.  SAP identifies the location and size of these aggregation prone regions, and allows us to perform target mutations of those regions to engineer proteins for enhanced stability.  We apply this method to therapeutic antibodies and demonstrate the significantly enhanced stability of our mutants compared to the wild type. The technology described here has the potential to enable the therapeutic use of proteins that are currently too unstable.  Moreover, it could be used to incorporate developability in a rational way during the screening of therapeutic proteins in the discovery phase for several diseases.

References:

1.  N. Chennamsetty, V. Voynov, V. Kayser, B. Helk and B. L. Trout, "Design of therapeutic proteins with enhanced stability", Proc. Natl. Acad. Sci. U.S.A., 106, 11937 (2009). This also appears as research highlight, "Unstuck by design", in Nature, 460, 155 (2009)

2.  N. Chennamsetty, B. Helk, V. Voynov, V. Kayser, and B. L. Trout, "Aggregation Prone Motifs in Human Immunoglobulin G", J. Mol. Biol., 391, 404 (2009).