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Dr. Arno Kromminga
Posted by Dr. Arno Kromminga BioAgilytix Insight, Immunogenicity

Webinar Recap: Your Questions About Unwanted Drug-Induced Immune Responses

Webinar Recap: Your Questions About Unwanted Drug-Induced Immune Responses

Methods for the detection of drug-induced antibodies have become much more sensitive, but the question remains to be answered: are antibodies at this low concentration level clinically relevant? In my latest webinar in partnership with Bioanalysis Zone, I described how seeing the whole antibody landscape, including those antibodies present at low concentrations, can help guide us to identify clinically meaningful data and more accurately correlate immunogenicity with clinical impact. I thoroughly enjoyed fielding some excellent questions from all of the listeners at the end of my presentation, so I am taking this opportunity to expand upon some of my answers and share them with all of you here. The following are a sampling of questions I received during the session:

Why are all proteins potentially immunogenic?
The central question of immunology is why and how the immune system recognizes something as not belonging. We know that when introduced into the body, proteins and peptides are known to initiate unwanted immune responses because the immune system is able to identify and target any substance containing antigens. It is difficult if not impossible to predict which patients are going to end up with an immunogenic response, which can range from loss of efficacy to fatal outcomes. We are constantly learning more about what factors can trigger these responses including those related to the drug itself and the individual patient (i.e., genetic predisposition).

Why is it important to measure low levels of anti-drug antibodies (ADA)?
As diseases and disorders progress, antibodies mature and reach a higher titer level. However, because early disease treatment is preferable, it is necessary to look at these ADAs at an earlier stage, which generally means in low concentrations. The progression of rheumatoid arthritis (RA) is an apt example of why we need to measure low levels of ADA. If you treat patients early on with TNF-alpha inhibitors, you can stop the disease from impacting the patient with irreversible levels of bone erosion and joint damage. If you were to wait for the associated ADAs to reach a high level, therapies would not be as effective.

What is the expected sensitivity for ADA tests?
There is no clear guidance on the targeted sensitivity of NAb assays. Because of this lack of structure, there are often significant differences in the analytical sensitivity of an ADA assay and the corresponding NAb, especially when using a cell-based NAb assay. Using a non-cell based NAb assay format often leads to superior analytical sensitivities, however, in those cases, there might be a gap between the ADA assay and the NAb assay. Regardless, any immunogenicity data needs to be integrated into the context of clinical manifestation and PKPD measurements.

Why are some ADAs binding and others neutralizing (NAbs), and which are more of a concern?
We see differences in the ADA (binding) assay and the NAb (functional) assay because of different analytical sensitivities. While the analytical sensitivity of ADA screening assays is often below 100ng/ml, the analytical sensitivity of NAb assays is in the high ng- or even low micro-range. As soon as we have similar analytical sensitivities, we may not be able to differentiate between binding and neutralizing antibodies. Additionally, during the process of antibody maturation, binding antibodies may develop to antibodies with neutralizing capacities due to higher affinities. Furthermore, “binding” ADA and NAb may bind to different epitopes. However, it is conceivable that some antibodies may bind to a drug without impacting binding to the drug target.

If a drug is not producing the desired therapeutic results according to the patient can’t we just raise the drug level?
The answer to this question depends on the available alternatives. We do have some biologicals for which there is no alternative drug. In this case, the best solution is to increase the dosage, but only because there is no other choice. If there are other options to manage the loss of efficacy or even cross-reactivity through the use of a new drug, that course of action is ideal. For example, when patients with Rheumatoid Arthritis and other inflammatory diseases experience a loss of efficacy, it is common to switch to a different drug because there are a multitude of alternative treatments available. Generally, this is seen as a more effective approach.

Do immunosuppressant drugs that are given to patients together with a therapeutic antibody affect ADA generation?
Generally, a co-medication with immunosuppressive drugs will lead to a reduction of the incidence rate of ADAs in response to a biological drug. We do have data from TNF-alpha inhibitors administered together with immune suppressants, which lead to a significant reduction of incidences from 30% to 3% for monoclonal drugs. Additionally, patients with impaired immune systems (e.g., cancer patients receiving chemotherapy) may be less likely to develop antibodies to therapeutic proteins than immuno-competent individuals.

Did you measure the presence of IgEs as they apply to allergic reactions due to glycosylations?
As we learned from the publication by Chung et al. in 2008, pre-existing IgE against exogenous carbohydrates may lead to anaphylactic reactions due to cross-reactivities of IgE antibodies towards glycosylation patterns. Therefore, the measurement of drug-specific IgE antibodies against biological drugs with an increased allergenic potential needs to be measured. Because the concentration of IgE antibodies is usually 2000-fold lower than IgG, very sensitive assays need to be used for the detection of IgE antibodies. Alternatively, a functional basophile activation test (BAT) can be used. The concentration of specific IgE is an indicator of the risk of developing an allergic reaction.

Thank you again to all of you who joined me for the live session and asked questions. Feel free to reach out to me directly with any additional insights about immunogenicity and inquiries about BioAgilytix’s related capabilities.

Download the On-Demand Webinar
To access the full recording of the live webinar and Q&A session, click here.

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