Photo-induced site-specific oxidative fragmentation of IgG1 mediated by iron(III)-containing histidine buffer: Mechanistic studies and excipient effects.
Eur J Pharm Biopharm
; 190: 121-130, 2023 Sep.
Article
em En
| MEDLINE
| ID: mdl-37482364
ABSTRACT
Fragmentation may compromise the clinical efficacy and safety profile of monoclonal antibodies (mAbs). We recently reported that Fe(III)-containing histidine (His) buffer mediates site-specific mAb fragmentation within the Fc domain when exposed to visible light (Y. Zhang and C. Schöneich, Mol. Pharm. 2023, 20, 650-662). Here, we show that this fragmentation proceeds even more efficiently under near-UV light. Several formulation strategies were applied in an attempt to reduce the photo-induced fragmentation. In solution formulations, the fragmentation can be mitigated by reducing the concentration of His buffer, adding Fe(III)-chelating agents, and replacing His with other amino acids. Fragmentation can be almost completely inhibited by formulating the protein in the lyophilized state. Mechanistically, His plays a critical role in the fragmentation process, likely due to its affinity for Fe(II), driving a photo-redox reaction towards product formation.
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Base de dados:
MEDLINE
Assunto principal:
Histidina
/
Ferro
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article