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Analytical Methods for Biological Drugs

Biopharmaceuticals, the majority of which are protein drugs, constitute a distinct class of medicines due to their complex nature and often large size. As a result, the synthetic route of production, which provides a high level of structural fidelity to small molecule medicines, is typically unavailable for protein drugs. Biotechnological manufacturing of protein drugs inevitably introduces some heterogeneity in the end-product, particularly at the level of post-translational modifications (PTM), which are very sensitive to the choice of protein expression systems.

The large size of biopharmaceutical products also inevitably results in increased frequency of post-production covalent modifications (non-enzymatic PTMs) that can occur as a result of storage and/or stress. In addition, protein therapeutics are prone to partial loss or destabilization of their higher order structure. Apart from the loss of function destablized proteins may also aggregate or trigger an immune response. The extreme importance of protein structure for efficacy and safety of biopharmaceuticals places a premium on the ability to characterize it at different levels, from primary structure (i.e., amino acid sequence and PTM) to conformation (secondary and tertiary structure) to correct assembly of multi-unit proteins (quaternary structure).

Structural characterization is also a key element throughout the drug discovery and design stages, as it enables optimization and enhancement of therapeutic properties. The analytical groups of Kaltashov and Vachet have developed an array of experimental methods based on mass spectrometry to probe structure of protein drugs and their interactions with therapeutic targets. The groups have a long history of collaborating with biopharmaceutical companies both in Massachusetts (Shire Human Genetic Therapies, Biogen IDEC) and beyond (Amgen, Regeneron, etc.).

 

Analytical Methods for Biological Drugs

Contact Info

Richard Vachet, Chemistry
(413) 545-2733
rwvachet@chem.umass.edu

Igor Kaltashov, Chemistry
(413) 545-1460
kaltashov@chem.umass.edu