Total ADA assays: solving the mystery of drug unresponsiveness

Jeremy Wright, Product and Sales Specialist, BIOHIT 

Therapeutic antibodies are widely used for treating a number of chronic inflammatory diseases –including arthritis, Crohn’s disease and ulcerative colitis – in patients that have not responded well to conventional therapies. For those suffering with inflammatory bowel disease, for example, these drugs have positive impacts on mucosal healing, pain reduction and quality of life, as well as on hospital admissions and general surgery.¹

Anti-inflammatory antibodies – a biopharmaceutical commonly referred to as ‘biologics’ in gastroenterology – block the effects of pro-inflammatory cytokines, such as tumour necrosis factor alpha (TNFα) and interleukins. Unfortunately, the body’s immune system can sometimes develop anti-drug antibodies (ADAs) that affect the pharmacokinetics, pharmacodynamics and efficacy of the drug, blocking its action and increasing the rate at which it is removed from the body. This reduces the circulating drug concentration, eventually leading to treatment failure, making the clinical management of inflammatory diseases extremely challenging. For instance, one study found that up to 46 per cent of patients with Crohn’s disease stopped responding to anti-TNFα therapies within a year.² Another study observed that 63 per cent of patients were still in non-remission after 54 weeks, and a further 8 per cent curtailed treatment due to severe adverse side effects.¹

Prioritising patient care

Highly specific serological ADA assays are valuable investigative tools for monitoring a patient’s immune response and detecting antibodies that might interfere with the action of biological anti-inflammatory drugs. This knowledge then aids care optimisation, such as increasing the dosage or dose frequency. It also directs treatment personalisation – for example administering immunosuppressants alongside anti-TNFα biologics – to prevent further development of ADAs before disease flare ups or adverse reactions. Routine ADA testing on blood samples ultimately informs safer, more cost-efficient usage of biologics for ADA-positive patients, and contributes to greater treatment success in the long run.

Some ADA assays measure circulating free ADAs which are not drug-bound. This means that circulating drugs affect the assay’s ability to detect ADAs, particularly with low titres or early-phase immunogenicity. Therefore, measurements for these assays should be taken when the circulating drug is at its lowest level – the ‘trough’ level – to reduce the likelihood of interference from the drug itself. A high circulating drug concentration can mask the presence of ADAs. This means there is a risk that the assay will produce false negative results. Clinicians then have to turn detective to identify why a patient demonstrates drug unresponsiveness despite their apparently low, or negative, ADA levels.

An emerging solution

This is where drug-tolerant total ADA assays have an advantage. Total ADA assays include a step to dissociate the drug from the bound ADA before analysis. This means that circulating drugs do not inhibit the assay’s function,  making it more sensitive to both free and bound ADAs. Patients can therefore be tested at any time, even when titres are low, enabling immunogenicity to be identified sooner and more accurately. This ultimately helps to predict possible future loss of treatment response.^1,3

Unfortunately, some biological anti-inflammatory drugs lend themselves more easily to the development of ADA assays than others. For instance, both free and total ADA assays are currently available for infliximab, adalimumab and ustekinumab, but there are only free ADA assays for vedolizumab and golimumab. The reasons behind this are multifactorial. Firstly, it is highly expensive to develop and validate new diagnostic assays. Secondly, many biotherapies are relatively new and have only been approved and on the market for a few years. Researchers therefore simply haven’t had the opportunity to develop total ADA assays for these novel treatments yet.

Additionally, there is a shortage of ADA-positive patients for assay validation, and newer and less-used drugs lack reference standards. It can take a long time for immunogenicity and reduced drug responsiveness to manifest. Plus, biological drugs are designed to be as non-immunogenic as possible. This means that it may be some time before sufficient numbers of patients are available for new total ADA assay trials.

The road ahead

Free ADA assays certainly have a role to play in the investigation of immunogenic response to biologics. However, developing and validating more total ADA assays for pre-emptive treatment strategies could be a major area of future research. Total ADA assays are bringing us nearer to a much-needed solution for immune-driven drug failures, and promise huge benefits for patients and healthcare systems alike.

To learn more about total-ADA assays, visit:

https://biohithealthcare.co.uk/products/therapeutic-drug-monitoring/

References

1. Kennedy, NA et al. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol. 4(5):341-353. doi: 10.1016/S2468-1253(19)30012-3. Epub 2019 Feb 27.
2. Ben-Horin, S and Chowers, Y. 2011. Review article: loss of response to anti-TNF treatments in Crohn’s disease. Aliment Pharmacol Ther. 33(9):987-95. doi: 10.1111/j.1365-2036.2011.04612. x. Epub 2011 Mar 2. PMID: 21366636.
3. Kharlamova, N et al. 2020. Drug Tolerant Anti-Drug Antibody Assay for Infliximab Treatment in Clinical Practice Identifies Positive Cases Earlier. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2020.01365