Abstract:
:Metal ions that leach into biotherapeutic drug product solution during manufacturing and storage, result in contamination that can cause physico-chemical degradation of the active molecule. In this review, we describe various mechanisms by which metal ion leachates can interact with therapeutic proteins and antibodies. Site-specific modifications due to metal catalyzed oxidation (MCO) of the therapeutic proteins cause them to become destabilized and potentially increasingly aggregation prone. We have examined the molecular sequences and structures for three case studies, human relaxin (hRlx), human growth hormone (hGH) and an IgG2 mAb to rationalize the experimental findings related to their MCO. The analysis indicates that metal-binding sites lie in close spatial proximities to predicted aggregation prone regions in these molecules. From the perspective of pharmaceutical development of biotherapeutic drugs, this link between molecular origins of MCO and subsequent aggregation is undesirable. This article further suggests molecular design strategies involving disruption of APRs that may also help mitigate the impact of metal ion leachates on biotherapeutic drug products as well as improving their solubility.
journal_name
Curr Pharm Desjournal_title
Current pharmaceutical designauthors
Kumar S,Zhou S,Singh SKdoi
10.2174/13816128113199990063subject
Has Abstractpub_date
2014-01-01 00:00:00pages
1173-81issue
8eissn
1381-6128issn
1873-4286pii
CPD-EPUB-20130522-1journal_volume
20pub_type
杂志文章,评审abstract::Obesity, insulin resistance, glucose intolerance/type 2 diabetes and hypertension are clustered in the metabolic syndrome representing critical risk factors for increased incidence cardio-cerebro-vascular diseases, kidney failure and cancer. Ectopic fat accumulation, i.e., accumulation in the mediastinum, liver and th...
journal_title:Current pharmaceutical design
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abstract:: ...
journal_title:Current pharmaceutical design
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