Our staff members have contributed to a number of scientific publications before and during their association with Coriolis. This combined knowledge is the backbone of our scientific excellence. If you are interested in reprints of the publications, please feel free to contact us.
Our most recent publications are listed below by default. Please make use of the drop-down filter to explore all our papers by year of publication or highlight some award winning key publications.
Pharm Res. 2015 Apr;32(4):1383-94. doi: 10.1007/s11095-014-1541-x (2015)
Small amounts of sub-visible aggregates enhance the immunogenic potential of monoclonal antibody therapeutics
Ahmadi M , Bryson CJ , Cloake EA , Welch K , Filipe V , Romeijn S , Hawe A , Jiskoot W , Baker MP , Fogg MH
Determine the effect of minute quantities of sub-visible aggregates on the in vitro immunogenicity of clinically relevant protein therapeutics.
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.
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.
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.