Metal‐catalyzed oxidation of human growth hormone: Modulation by solvent‐induced changes of protein conformation

Stability of Protein Pharmaceuticals: An Update

“…The ligands are often Gly, Asp, His and Cys. Of these amino acids, His and Cys are sensitive to oxidative damage, as the ROS generated at the metal center does not have to diffuse very far before reacting with the protein (211). Mechanistic studies show that the metal ion and peroxides undergo a Fenton-type reaction, creating free radicals (212).…”

“…The products of the oxidation of His are varied (213), but 2-oxo-His appears to be the major oxidation product. The 2-oxo-His product has been detected in human relaxin (214), prolastin (215) and human growth hormone (211,216).…”

“…Keep in mind that the binding affinity of EDTA decreases significantly below pH 5, where the carboxylate side chains become protonated. Note that antioxidants, such as ascorbate, while effective at reducing lipid peroxidation, can actually increase the reactivity of transition metals and increase MCO-mediated damage (211,(244)(245)(246). Otherwise, minimizing the levels in the bulk drug and excipients used is the other factor that will lead to improved storage stability with respect to oxidation.…”

Site-Specific Tryptophan Oxidation Induced by Autocatalytic Reaction of Polysorbate 20 in Protein Formulation

“…Oxidation of methionine (Met) in pharmaceutical proteins such as relaxin, interleukin-2, parathyroid hormone, trastuzumab, Orthoclone OKT3, nerve growth factor, insulin-like growth factor I, and human growth hormone has been well characterized and studied (1)(2)(3)(4)(5)(6)(7)(8)(9). In contrast, oxidation of Trp in pharmaceutical proteins is less common due to its slow reaction at low temperature (10) and low reactivity of the amino acid residue with peroxides.…”

Comparative Evaluation of Disodium Edetate and Diethylenetriaminepentaacetic Acid as Iron Chelators to Prevent Metal -Catalyzed Destabilization of a Therapeutic Monoclonal Antibody

“…However, excessive iron may become toxic or even fatal due to its ability to induce oxidation of lipids and other cellular constituents [8][9][10] . It has been reported that iron can induce protein degradation via different mechanisms [11][12][13][14][15] . Since iron is only regulated by uptake 6 , iron chelators have been introduced into clinical practice to protect patients from toxicity caused by iron overload.…”