Abstract
Biological molecules are increasingly becoming a part of the therapeutics portfolio that has been either recently approved for marketing or those that are in the pipeline of several biotech and pharmaceutical companies. This is largely based on their ability to be highly specific relative to small molecules. However, by virtue of being a large protein, and having a complex structure with structural variability arising from production using recombinant gene technology in cell lines, such therapeutics run the risk of being recognized as foreign by a host immune system. In the context of immune-mediated adverse effects that have been documented to biological drugs thus far, including infusion reactions, and the evolving therapeutic platforms in the pipeline that engineer different functional modules in a biotherapeutic, it is critical to understand the interplay of the adaptive and innate immune responses, the pathophysiology of immunogenicity to biological drugs in instances where there have been immune-mediated adverse clinical sequelae and address technical approaches for their laboratory evaluation. The current paradigm in immunogenicity evaluation has a tiered approach to the detection and characterization of anti-drug antibodies (ADAs) elicited in vivo to a biotherapeutic; alongside with the structural, biophysical, and molecular information of the therapeutic, these analytical assessments form the core of the immunogenicity risk assessment. However, many of the immune-mediated adverse effects attributed to ADAs require the formation of a drug/ADA immune complex (IC) intermediate that can have a variety of downstream effects. This review will focus on the activation of potential immunopathological pathways arising as a consequence of circulating as well as cell surface bound drug bearing ICs, risk factors that are intrinsic either to the therapeutic molecule or to the host that might predispose to IC-mediated effects, and review the recent literature on prevalence and intensity of established examples of type II and III hypersensitivity reactions that follow the administration of a biotherapeutic. Additionally, we propose methods for the study of immune parameters specific to the biology of ICs that could be of use in conjunction with the detection of ADAs in circulation.
Highlights
Immunogenicity is antigenicity in an inflammatory milieu resulting in a successful humoral response
Macrophages, and polymorphonuclear cells that express activating Fc receptors (FcRs) produce proinflammatory cytokines in particular interferon (IFN)-γ that induces the expression of Class II MHC that further enhances the antigen uptake, processing, and presentation – eventually exacerbating a weak anti-drug antibodies (ADAs) response. (b) immune complex (IC) carrying multiple therapeutic proteins can cross-link cognate B cell receptor (BCR) on the B cells producing the ADA, causing co-clustering of the BCR Ig alpha and beta chains leading to further activation of the B cells and more ADA (Figure 1)
The examples covered in this article will focus on two scenarios on how IC formed by the ADA with the drug translates to a poor clinical outcome; one where binding by neutralizing ADA results in abrogation of pharmacological activity of the drug and second where the ADA causes sequestration of the therapeutic by formation of an IC with the drug, and causing enhanced clearance resulting from recognition of ICs by FcR
Summary
Immunogenicity is antigenicity in an inflammatory milieu resulting in a successful humoral response. Most adverse effects consequential to ADA formation, such as pharmacological abrogation, impact on therapeutic exposure, or hypersensitivity reactions, are a consequence of formation of immune complexes (ICs) between the ADA and therapeutic protein Their levels, kinetics of interaction, size, polyclonal diversity, distribution, and Fc-mediated physiological effects can be potentially translated to clinically observable adverse effects. ADA bound to drug in circulation gives rise to circulating ICs (CICs) and they can result in type III reactions Regardless of their presence, ICs are relevant from two main points of analysis – their size and their propensity to activate complement. The case reports will focus on those where the clinical presentation represents an underlying type I or type II hypersensitivity
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