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Antidrug Antibodies
Measuring Antidrug Antibodies During Anti-TNF Therapy

Released: February 16, 2022

Expiration: February 15, 2023

Marla Dubinsky
Marla Dubinsky, MD
Bruce E. Sands
Bruce E. Sands, MD, MS
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Among the key tools for therapeutic drug monitoring, particularly for anti-TNF agents, are clinical assays that measure serum levels of both the drug and antidrug antibodies (ADAs)—but not all assays are the same. 

Measuring Drug Levels
From the perspective of measuring anti-TNF drug levels, the assays are more alike than different. From assay to assay, you can look at drug levels and essentially know whether the serum drug concentration is in a good range. They match up pretty well. 

Some would say that—the current drug level (typically, at the trough)—is ultimately what you need to know. However, decisions informed by drug levels must be made in the context of other clinical parameters, including inflammation and ADA levels, and measuring ADAs is where these assays differ most.

Measuring ADA Levels
There are different methodologies to measure ADA levels, including enzyme-linked immunosorbent assay (ELISAs), electrochemiluminescence immunoassays (ECLIAs), and homogenous mobility shift assays (HMSAs), but—of importance—some are drug tolerant and others are not. Drug-tolerant assays can accurately measure ADAs in the presence of drug, whereas drug intolerant assays cannot. It follows that there is intertest variability in what levels of ADAs are considered below a certain threshold. We suggest learning to use 1 or 2 assays well so that, over time, you understand the meaning of the results. However, in practice, you cannot directly translate an ADA concentration readout from one assay to another.

Interpreting Assay Results
Identifying a low titer of ADAs in the presence of detectable drug can be difficult to interpret. There is some evidence that the detection of ADAs, even in the presence of circulating drug, portends a loss of response over time and is associated with high levels of inflammation already present—for example, as measured by C-reactive protein. It could be that the ADA level will rise higher over time and that the drug level could then drop, leading to a loss of response. In that circumstance, you might consider intervening proactively to inhibit the low-titer ADAs, such as by adding an immunomodulator, adjusting the dosing frequency, or increasing the dose.

On the other hand, the ADAs could be non-neutralizing, such that they do not hinder therapeutic activity of the drug, and presumably they are clinically insignificant. Indeed, in the phase IIIb SEAVUE trial of ustekinumab vs adalimumab in patients with moderate to severe Crohn disease, patients in the adalimumab arm had considerably higher rates of ADAs than those in the ustekinumab arm (>60% vs 2%). Yet, there was no significant difference in the efficacy of the 2 drugs. Hence, the assay used for adalimumab (which was highly sensitive) probably was not detecting neutralizing antibodies. Moreover, regarding ustekinumab, it is worth mentioning that we are uncertain of the role of testing for ADAs with this and other non–anti-TNF drugs.

Low levels of antibodies detected by non–radio-labeled liquid-phase mobility shift assays merit more exploration. However, if there is measurable drug, the antibodies most likely are not neutralizing.

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