Optimal Formulation and Quality Control of Whole Potein Therapeutics with DXMS

Whole proteins, including monoclonal antibodies, are the fastest-growing class of therapeutics. Compared with traditional small molecule drugs, much additional analysis is necessary for their development and production due to their large size and complex structure. The protein construct and its formulation have to be optimized during development, and its structural integrity must be closely monitored during production.

DXMS is the ideal analytical tool to monitor protein's structural integrity in the development and production of whole protein therapeutics. During development, DXMS data can rapidly determine the effects of mutation, chemical modification, and/or formulation change on protein folding/dynamics, and localize any changes at the submolecular level. During production, DXMS can be a rapid and sensitive method to identify batch-to-batch variation in protein folding. The foregoing studies of hGH exemplify the use of this technology for formulation optimization. In this case, the H/D exchange data allowed close monitoring of the changes induced by pH alteration.

Many blockbuster protein therapeutics will soon be coming off-patent. It is unclear how regulatory agencies might best evaluate and approve generic versions of these complex pharmaceuticals. Inventor companies assert that the production process must be precisely reproduced for biophysical and pharmaceutical equivalence, and argue that experimentally proving equivalence of their formulation versus potential generic whole protein therapeutics is impossible. From this perspective, generic protein therapeutics have to undergo costly clinical trials for demonstration of efficacy and safety. Generic companies assert that experimentally demonstrating the equivalence between original and generic protein therapeutics by biophysical and biochemical measurements in the laboratory is possible as is now done with small molecule generics, a much less costly proposition. It is possible that DXMS will prove to be capable of establishing the structural equivalence (or lack thereof) between original and generic versions of these protein therapeutics.

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