Oxidation of protein- and peptide-based drug products can lead to reduced quality and stability, which can alter their immunogenicity and safety profiles. Many different protein oxidation products and different analytical tools have been identified in separate studies, including oxidation of specific residues, carbonylation of specific residues, and oxidative cleavage of peptide bonds. We undertook a comprehensive examination of large protein oxidation, including analyses of multiple products of protein oxidation across several model oxidizing systems, in order to establish quantitative measurements of protein oxidation products within each system and to determine the kinetics of each sub-set of oxidation products. Various oxidation conditions (e.g. metal-catalyzed oxidation, organic peroxides) were analyzed via time course experiments to determine general rates of formation for different protein oxidation products (e.g. methionine sulfoxide, carbonylation) under each condition. Rates and types of oxidative damage were then correlated with activity and structural analyses to determine the contributions of each oxidative product towards potential activity abrogation and structural perturbations. Rates of formation and relative contributions of oxidation products to activity abrogation can inform the sensitivity of protein-based drug products to destabilizing oxidative conditions and be used to select stabilizers for the prevention of oxidative damage.

Impacts of protein oxidation conditions on structure and function

254th National Meeting (2017)

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