title: Effects of localized interactions and surface properties on stability of protein-based therapeutics.
abstract: OBJECTIVE
  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. This review identifies and highlights individual chemical attributes and categorizes how site-specific changes affect protein stability based on published high-resolution molecular analyses.
  
  
  RESULTS
  Because it is challenging to determine the mechanisms by which the stability of large, complex molecules is altered and data are sparse, smaller, therapeutic proteins (insulin, erythropoietin, interferons) are examined alongside antibody data. Integrating this large pool of information with the limited available studies on antibodies reveals common mechanisms by which specific alterations affect protein structure and stability.
  
  
  CONCLUSIONS
  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 on/near the surface of proteins have substantial influence on structure and stability. Seemingly small, superficial modification 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 or higher order protein structure.
authors.affiliation: Department of Chemistry, The University of Kansas, Lawrence, KS, USA.
authors.forename: Brittney J
authors.initials: BJ
authors.lastname: Mills
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, USA.|BioAnalytix Inc., Cambridge, MA, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Laurence Chadwick
mesh_terms: D000906:Antibodies / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000737:chemistry*; D055550:Protein Stability; D011506:Proteins / Q000008:administration & dosage / Q000737:chemistry*; D012995:Solubility; D013499:Surface Properties
chemical_list: D000906:Antibodies; D018796:Immunoconjugates; D011506:Proteins
keywords: biomedicinal chemistry; biotechnology and drug discovery; drug characterisation studies; pharmaceutical analysis