Immunogenicity is an inflammatory antigenicity evoking a humoral response in the body. Anti-drug antibodies (ADA) can also be evoked in vivo to a biotherapeutic. This elicited response is generally a measure of immunogenicity. Newer multi-domain therapeutics, protein therapeutic platforms, and a rise in investment and technology for developing drugs with minimal side effects are the primary reasons for the increasing relevance of immunogenicity assay development.
ADA plays a vital role in immunogenicity and allergic reactions to biologic therapies. After considering associated immunogenic risk factors, ADA ELISA assays detect, report, and characterize ADAs via a tiered approach. ADA CROs incorporate several bioanalytical assays such as Meso Scale Discovery ADA bridging assay, confirmatory ADA assay, tolerance ADA assays, and Nab assay development in ADA evaluation. The following sections highlight these roles in more detail.
Role of PK ADA in Immunogenicity
Most detrimental effects due to ADA formation, such as hypersensitivity reactions, pharmacological abrogation, or impact on therapeutic exposure, are because of the formation of immune complexes between therapeutic protein and ADAs. Their level of interaction, kinetics, distribution, size, polyclonal diversity, and physiological effects can be translated into observable adverse effects. These interactions give rise to immunogenicity. Immunogenicity is the generation of ADAs due to therapeutic exposure, which in turn forms immune complexes that mediate adverse effects.
Studies have evaluated multiple molecular pathways underlying immune complexes of several autoimmune conditions. Although detecting specific immune complexes has remained challenging, the ADA method focuses on other quantifiable PK ADA biomarkers that mediate innate and adaptive immune responses. These biomarkers can either reflect immune complex formation or their downstream effects. However, the primary objective is to identify the degree and intensity of their involvement in generating immune responses.
The final goal is identifying and characterizing these molecular pathways that can be appropriately integrated and applied across several immunogenicity risk management processes. Today the biotechnology industry has made considerable progress in identifying and mitigating numerous risk factors such as biophysical character, route of delivery, formulation, and binding sequences to multiple MHC alleles.
However, several host-specific phenotypic markers, such as the distribution of Class II alleles. Some can also be polymorphic. These host characteristics might explain the variability in the downstream effects due to ADA levels or influence the behavior and formation of immune complexes. Identifying and characterizing these influences must be considered while developing a total risk assessment protocol.
ADAs can generate type II and type III reactions. Cell surface protein target-bound therapeutic molecules can attract ADAs. This attraction leads to the formation of immune complexes on cell membranes, and adverse effects due to these reactions are termed type II reactions. When ADAs are bound to a drug in circulation, they may give rise to circulating immune complexes, which are classified as type II reactions.
Irrespective of their presence, immune complexes are characterized based on their size and ability to activate the complement system. Both these factors result in immune complex deposits and activate inflammatory pathways. Moreover, the size of immune complexes affects Fc-mediated responses. These responses are mediated through interactions with a broad family of activating Fc receptors. The level of Fc receptors varies from individual to individual.