| Autor: |
Ahmadi, Maryam, Bryson, Christine, Cloake, Edward, Welch, Katie, Filipe, Vasco, Romeijn, Stefan, Hawe, Andrea, Jiskoot, Wim, Baker, Matthew, Fogg, Mark |
| Předmět: |
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| Zdroj: |
Pharmaceutical Research; Apr2015, Vol. 32 Issue 4, p1383-1394, 12p |
| Abstrakt: |
Purpose: Determine the effect of minute quantities of sub-visible aggregates on the in vitro immunogenicity of clinically relevant protein therapeutics. Methods: Monoclonal chimeric (rituximab) and humanized (trastuzumab) antibodies were subjected to fine-tuned stress conditions to achieve low levels (<3% of total protein) of sub-visible aggregates. The effect of stimulating human dendritic cells (DC) and CD4 T cells with the aggregates was measured in vitro using cytokine secretion, proliferation and confocal microscopy. Results: Due to its intrinsic high clinical immunogenicity, aggregation of rituximab had minimal effects on DC activation and T cell responses compared to monomeric rituximab. However, in the case of trastuzumab (low clinical immunogenicity) small quantities of aggregates led to potent CD4 T cell proliferation as a result of strong cytokine and co-stimulatory signals derived from DC. Consistent with this, confocal studies showed that stir-stressed rituximab was rapidly internalised and associated with late endosomes of DC. Conclusions: These data link minute amounts of aggregates with activation of the innate immune response, involving DC, resulting in T cell activation. Thus, when protein therapeutics with little or no clinical immunogenicity, such as trastuzumab, contain minute amounts of sub-visible aggregates, they are associated with significantly increased potential risk of clinical immunogenicity. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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