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Qualitative Insights on ADA Assay for Immunogenicity Testing
2 Dec 2020

Immunogenicity testing and ADA assays play a critical role in biologic drug development. This is especially true for biopharmaceuticals, which are seeing increasing development. The larger molecules employed in these therapies can trigger the human body’s defense mechanisms and elicit a response. 

The immune response thus creates anti-drug antibodies (ADA). This can cause the creation of larger molecules that change the underlying properties of the drug, or a more dangerous combination. With the body itself fighting against the drug, its efficacy is lowered or negated. Implications of the ADA response also include altering the pharmacokinetic (PK) and pharmacodynamic (PD) profile of the drug. 

Immunogenicity testing is employed in the pre-clinal phase of drug development to check for this response. It is common to apply immunogenicity assays to detect ADAs and consider the future course of action.

Qualitative Approach of ADA Assays

In January 2019, the FDA finalized a series of non-binding guidelines for the industry to employ. The guideline deals with developing and validating assays for ADA detection. Generally speaking, immunogenicity assays or tests are designed to find antibodies that could have a neutralizing effect on the drug. 

The process generally begins with the use of screening ADA assay designed to find ADAs that bind to the drug. Specificity and sensitivity of the screening assay are important in verifying the presence of antibodies. Screening assays can be qualitative and simply declare the presence (or lack thereof) of the antibody. 

There is always a chance of getting a false-positive, so a confirmatory assay is employed. Confirmatory assays should have a higher degree of specificity and selectivity when compared to the screening assays.

Further analysis can be performed as necessary with the use of titration assays and neutralization assays. The latter looks at the ADA’s potential in neutralizing the therapy/drug. Titration assays present the magnitude of the antibody response. Other characterizing assays may be performed as necessary. Assay optimization may be necessary in some cases to account for specific parameters.

In the case of products with multiple domains, the testing process becomes more complex. It is desirable to perform multiple tests. 

Establishing Threshold Values and Cut Points

Since ADA assays can be qualitative, it is important to set up cut points (threshold values) to determine a positive or negative result of the immunogenicity testing.  Here are a few other factors worth considering: 

The presence of pre-existing antibodies is one such factor. Natural antibodies may be present due to several reasons. However, they need to be accounted for setting up cut points. It may also be necessary to employ more assays or using quantitative assays over qualitative ones.  

Another factor is the target disease cut point. People can have different immune responses. One of the reasons can be differing immune responses from people with autoimmune diseases or other issues that cause higher background immunoreactivity than the normal person. Thus, setting cut points that respond with a target disease can be useful. Finally, it is fruitful to make the correct use of statistical methods to ensure better results with cut points and the overall approach in general. 

ADA assay assays immunogenicity
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