Article Addenda

Predictive tools for stabilization of therapeutic proteins

Volume 1, Issue 6   November/December 2009
Pages 580 - 582
http://dx.doi.org/10.4161/mabs.1.6.9773
Authors: Vladimir Voynov, Naresh Chennamsetty, Veysel Kayser, Bernhard Helk and Bernhardt L. Trout

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Abstract:
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.

Article Addenda to:
N Chennamsetty, V Voynov, V Kayser, B Helk, BL Trout. Design of therapeutic proteins with enhanced stability. Proc Natl Acad Sci U S A 2009; 106: 11937-42
PMID: 19571001 DOI: 10.1073/pnas.0904191

Received: August 10, 2009; Accepted: August 10, 2009

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