Effects of Localized Interactions and Surface Properties on Stability of Protein-Based Therapeutics

摘要

Protein-based therapeutics garner significant attention because of exquisite specificity and limited side effects and are now being used to accomplish targeted delivery of small molecule drugs. Physical and chemical stability of therapeutic proteins and antibody drug conjugates (ADCs) is of critical importance because insufficient stability prevents molecules from making it to market. Individual moieties onear the surface of proteins have substantial influence on stability. Seemingly small, superficial modification of the protein may have far-reaching consequences on structure, conformational dynamics, and solubility of the protein, and hence physical stability of the molecule. Chemical modifications, whether spontaneous (e.g. oxidation, deamidation) or intentional, as with ADCs, may adversely impact stability by disrupting local surface properties and/or higher-order protein structure. Because it is challenging to determine at high resolution the mechanisms by which the stability of large, complex molecules, particularly ADCs, is altered and data is sparse, in this review detailed studies of smaller, therapeutically relevant proteins such as insulin, erythropoietin, and the interferons are presented along with antibody data. Considering this large pool of data along with the limited available studies on antibodies demonstrates common mechanisms by which specific alterations to proteins affect their structure and stability and may be relevant to ADCs.