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Review
. 2022 Nov;36(6):731-748.
doi: 10.1007/s40259-022-00559-1. Epub 2022 Oct 31.

Assessing Immunogenicity of Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine

Johanna Elin Gehin  1 , Guro Løvik Goll  2 , Marthe Kirkesæther Brun  2   3 , Meghna Jani  4   5 , Nils Bolstad  6 , Silje Watterdal Syversen  2
Affiliations
Review

Assessing Immunogenicity of Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine

Johanna Elin Gehin et al. BioDrugs. 2022 Nov.

Abstract

Biologic drugs have greatly improved treatment outcomes of inflammatory joint diseases, but a substantial proportion of patients either do not respond to treatment or lose response over time. Drug immunogenicity, manifested as the formation of anti-drug antibodies (ADAb), constitute a significant clinical problem. Anti-drug antibodies influence the pharmacokinetics of the drug, are associated with reduced clinical efficacy, and an increased risk of adverse events such as infusion reactions. The prevalence of ADAb differs among drugs and diseases, and the detection of ADAb also depends on the assay format. Most data exist for the tumor necrosis factor-alpha inhibitors infliximab and adalimumab, with a frequency of ADAb that ranges from 10 to 60% across studies. Measurement of ADAb and serum drug concentrations, therapeutic drug monitoring, has been suggested as a strategy to optimize therapy with biologic drugs. Although the recent randomized clinical Norwegian Drug Monitoring (NOR-DRUM) trials show promise towards a personalized medicine prescribing approach by therapeutic drug monitoring, several challenges remain. A plethora of assay formats, with widely differing properties, is currently used for measuring ADAb. Comparing results between different assays and laboratories is difficult, which complicates the development of cut-offs necessary for guidelines and the implementation of ADAb measurements in clinical practice. With the possible exception of infliximab, limited data on clinical relevance and cost effectiveness exist to support therapeutic drug monitoring as a routine clinical strategy to monitor biologic drugs in inflammatory joint diseases. The aim of this review is to provide an overview of the characteristics and prevalence of ADAb, predisposing factors to ADAb formation, commonly used assessment methods, clinical consequences of ADAb, and the potential implications of ADAb assessments for everyday treatment of inflammatory joint diseases.

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Conflict of interest statement

GLG has received honoraria, consulting fees, and payment for lectures from Pfizer, AbbVie, Boehringer Ingelheim, Roche, Orion Pharma, Sandoz, Novartis, and UCB, all unrelated to the present work. JEG, MKB, MJ, NB, and SWS report no relevant disclosures.

Figures

Fig. 1
Fig. 1
Immunoassay formats used for anti-drug antibody (ADAb) detection. a In antibody capture tests, ADAb is “captured” by binding to a solid-phase bound biologic drug, and quantified by labeled anti-human antibody tracers. b In the bridging test, ADAb are detected by cross-linking of the solid-phase and labeled biologic drug molecules. c In the antigen-binding test, human immunoglobulins are captured by protein A (or anti-human antibody) coated sepharose beads. After non-bound serum components are washed off, ADAb are detected by binding to labeled biologic drug/fragment. d In the inhibition test, samples are preincubated with a known amount of labeled biologic drug. Anti-drug antibodies inhibit binding of a labeled biologic drug to its target molecule (e.g., tumor necrosis factor alpha [TNFα]). The signal is thus inversely proportional to the amount of ADAb in the sample. Assay antibodies are illustrated as intact immunoglobulins, but immunoglobulin fragments are preferred in most formats. Created with BioRender
Fig. 2
Fig. 2
Model of the relationship between anti-drug antibody (ADAb) development, decrease in tumor necrosis factor alpha inhibitor (TNFi) serum concentration, and subsequent loss of clinical response. a Free circulating TNFi in sample. b Incipient ADAb formation. TNFi and ADAb in complexes. c Free ADAb becomes detectable using drug-sensitive assays (when TNFi undetectable/very low). Anti-drug antibodies can presumably be detected earlier using drug-tolerant assays. The clinical effect of the drug diminishes when the concentration of TNFi becomes subtherapeutic (the relative amount of ADAb is higher than free TNFi). Created with BioRender
Fig. 3
Fig. 3
Suggested algorithm for the interpretation of tumor necrosis factor inhibitor (TNFi) levels and anti-drug antibodies (ADAb) in responders or non-responders to TNFi. a Proactive therapeutic drug monitoring; regular measurements with subsequent dose optimization and b reactive therapeutic drug monitoring; measurements in response to particular clinical situations, such as a suspected treatment failure
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