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Predictive tools for stabilization of therapeutic proteins

Vladimir Voynov, Naresh Chennamsetty, Veysel Kayser, Bernhard Helk and Bernhardt L. Trout

Monoclonal antibodies represent the fastest growing class of pharmaceuticals.  A major problem, however, is that the proteins are susceptible to aggregation at the high concentration commonly used during manufacturing and storage.  Our recent publication describes a technology based on molecular simulations to identify aggregation-prone regions of proteins in silico.  The technology, called spatial aggregation propensity (SAP), identifies hot-spots for aggregation based on the dynamic exposure of spatially-adjacent hydrophobic amino acids.  Monoclonal antibodies (mAbs) in which patches with high-SAP scores are changed to patches with significantly reduced SAP scores via a single mutation are more stable than wild type, thus validating the SAP method for mapping aggregation-prone regions on proteins.  We propose that the SAP technology will be useful for protein stabilization, and as a screening tool to bridge discovery and development of protein-based therapeutics by a rational assessment of the developability of candidate protein drugs.

Design of therapeutic proteins with enhanced stability. Chennamsetty N, Voynov V, Kayser V, Helk B, Trout BL. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):11937-42.

Authors

Vladimir Voynov

Massachusetts Institute of Technology

Naresh Chennamsetty

Massachusetts Institute of Technology

Veysel Kayser

Massachusetts Institute of Technology

Bernhard Helk

Novartis Pharma AG

Bernhardt L. Trout Corresponding author: trout@mit.edu

Massachusetts Institute of Technology