Abstract:
:Recent oxidation events on monoclonal antibody candidates prompted us to investigate the mechanism of oxidation of Met, Trp, and His residues and to search for suitable stabilizers. By using parathyroid hormone (1-34), PTH, as a model protein and various oxidants, aided by liquid chromatography, peptide mapping, and mass spectrometry, we identified and quantified the oxidation of these vulnerable residues. Whereas H(2)O(2) and t-butyl hydroperoxide (t-BHP) primarily oxidized the two Met residues, 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH), and H(2)O(2) + Fe(II) oxidized Met and Trp residues, with AAPH more capable of generating oxidized Trp species than the latter. H(2)O(2) + Fe(III) generated results comparable to those with H(2)O(2) + Fe(II), except that there was a lesser amount of hydroxylated Phe. Oxidation of the His residue in PTH occurred when copper was used instead of iron. AAPH, a free-radical generator, produced alkylperoxides, which simulated the oxidizing species from degraded polysorbate, commonly found in protein formulations. It is prudent to screen stabilizers by using H(2)O(2), H(2)O(2) + Fe(II), and AAPH because these agents represent potential assaults from the H(2)O(2) commonly present in degraded polysorbate, the residue of aseptic agents and the metal from stainless steel surfaces, and alkylperoxides from degraded polysorbate, respectively. Free Met protected the Met residues in PTH from oxidation by H(2)O(2) and H(2)O(2) + Fe(II). Mannitol and EDTA were effective against H(2)O(2) + Fe(II). Free Trp protected only the Trp residue in PTH from oxidation by AAPH, the combination of Trp and Met was effective against all three oxidant conditions. By using AAPH to generate oxidant, Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) and pyridoxine were also found to exhibit good free-radical scavenging activity and thus protected Trp in PTH against oxidation.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Ji JA,Zhang B,Cheng W,Wang YJdoi
10.1002/jps.21746subject
Has Abstractpub_date
2009-12-01 00:00:00pages
4485-500issue
12eissn
0022-3549issn
1520-6017pii
S0022-3549(16)33208-7journal_volume
98pub_type
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