Background Treatment with biological drugs in the last fifteen years has changed the therapy of most inflammatory diseases, mainly in the field of rheumatology. The use of these drugs has supposed a revolution in the treatment of disease, making this type of medication the fastest growing class of therapeutics today. Monoclonal antibodies targeting tumor necrosis factor (TNF) were among the first biologicals to appear on the market, and they are the most often used to date. They have proven to be powerful drugs applied to such inflammatory rheumatic diseases as rheumatoid arthritis, ankylosing spondylitis. All patients may benefit from routine measurement of serum trough levels of biologicals.
Immunogenicity. Drug and antibody levels Several methods have been developed to measure the serum concentration of these drugs, mainly by capture or sandwich ELISA, or a reported gene-based assay based on a bioluminescent reaction produced by cells growing in the presence of TNF. Many publications have associated the good clinical response of a treatment with biologics with the circulating amount of the drug.
However, biologics are recognized by the immune system as foreign and they provoke an immune response. Antibodies to the drugs (ADA) recognize strange sequences in the antigen-binding site of the monoclonal antibodies, or in the fusion part of the proteinconstructs. Besides the nature of the biological, antibody responses may also be influenced by patient-related factors such as genetic background, underlying disease, immunomodulating therapy, and dosing schedule. If a patient develops ADA, circulating levels of the biological will be less than expected or even absent in the serum. ADA can form a complex with the drug, thereby inhibiting drug activity, which can result in treatment failure. The production of ADA is associated with treatment failure, increased risk of infusion-related reactions and early drop-out of the treatment.
Two are the main methods used in the clinical routine to measure the appearance of ADA: bridging ELISA and Antigen Binding Test (ABT)). ELISA takes advantage of the fact that IgG1,2,3 isotypes can bridge the same molecule (the biological) by both arms. It is easy to perform and suitable to implement in any lab. Drawbacks of this system are the potentially false positive results given by rheumatoid factor and the difficulty to detect IgG4-ADA, because of its monovalency. ABT is based on the detection of the radiolabel drug to the serum antibody bound to protein A Sepharose beads. ABT detects IgG4-ADA as well as the other isotypes. However, with both kind of assays only excess of the antibody present in serum is detected, due to the drug interference. Complexes of ADA-drug are not detected in the assays to measure drug neither in the ADA assays. Although it is admitted that the therapeutic effect of a drug is associated with the amount of free drug available to bind the antigen (TNF), efforts are being made to develop assays that can detect the earliest production of antibodies, and to investigate its clinical relevance. These assays are based on the acid-dissociation of the complexes together with neutralization of the free drug before re-naturalization. However, if we realize that methods to measure ADA are still not well standardized, the most easy way to detect whether a patient is making ADA is to monitor the amount of the circulating drug levels at any moment of the treatment.
Analysis of the drug and antibody levels The most useful application of the measurement of drug and ADA in serum is the therapeutic drug monitoring (TDM) as a tool of personalized medicine to improve patient care by adjusting the drug dosage at the individual patient levels.
By performing this monitoring a range of the optimal amount of circulating drug – in relation with the clinical response – can be drawn, per patient and per kind of biological. This procedure will allow:
A) To avoid overtreatment or under treatment, both expensive procedures because of a waste of resources
B) To help the performance of switching in patients who are non-responders to the therapy. Patients not responding to therapy associated to ADA formation, may switch to a biological with a similar target. In contrast, non-responders with adequate drug levels who do not develop ADA may benefit from biologics with another mode of action.
C) To perform a dose tapering of the administered amount of drug in patients that enter in remission or maintain low clinical activity,
D) To help in the decision to increase the amount of drug when there are no other therapeutic options.
Thus all these options allow for a therapy optimization of individual patients. The personalized medicine approach benefits the patient and reduces costs associated to a more efficient therapy implementation.
Disclosure of Interest None declared