Pre-Clinical In-Vitro Studies on Parameters Governing Immune Complex Formation
Posted by Adam Awdish on
Mouse Non Swiss Albino Serum from Innovative Research was used in the following study:
Pre-Clinical In-Vitro Studies on Parameters Governing Immune Complex Formation
Marie Fichter, Gesa Richter, Alexander Bepperling, and Paul Wassmann
Pharmaceutics
June 13, 2022
Biotherapeutics provide an opportunity to make huge advancements in medical treatments, however, their development is often challenged by undesirable or unexpected immunogenic events that present themselves in patients. This is characterized by the formation of anti-drug antibodies (ADAs), which, under certain conditions, may cause the formation of immune complexes (ICs) that can trigger cascades with effects on various cell types. Unfortunately, the connection between ICs and their impact downstream in cascades is still not well understood. ADAs, on the other hand, may have no effect, alter pharmacokinetics, or lead to neutralization of the treatment’s efficacy.
Due to the inherent differences between animal and human immune systems, there is little predictive value in using animal studies for assessing new biotherapeutic treatments. Further, the potential immunogenic risks to healthy patients in studies during drug development pose a threat to the further development and approval of the treatment. Thus, there is a clear need for ways to gain insight into factors leading to the immunogenicity of biotherapeutic drug candidates.
The current best method for assessing the potential effects of new biotherapeutics is to test the drug candidate against other drugs with the same target. Multiple immunogenicity prediction tools may be used during this time, from amino acid sequence-focused bioinformatics to sophisticated in vitro cell-based analytical approaches like MAPPS or T cell-based assays. Unfortunately, these methods are limited by their diversity and interdependency on factors important for the activation of immunological responses. Additionally, although monitoring of free circulating ADAs in serum is critical during biotherapeutic clinical trials, the monitoring of ICs is currently not common practice.
There is a clear need for more in-depth methods of analyzing biotherapeutics before their developmental assessment and clinical trials. This study focused on the creation of a novel in vitro IC characterization platform that could be used to gain mechanistic insights into the relevance of different attributes of ICs when they form.
The attributes assessed included the IC’s absolute concentration of building blocks, the molar ratio between components, the quantity of neo-epitopes ADAs recognized, biotherapeutic material quality, the impact of the pharmacologic target antigen on IC formation, and the impact of serum components on IC formation. This was taken a step further when the researchers also assessed the performance and limitations of using mass photometry, SEC(-MALS), SV-AUC, and DLS to characterize ICs.
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