Ultimately, all biological drugs are immunogenic. Unwanted immunogenicity against therapeutic biological drugs is often characterized by antibodies, and over the last several years, methods for the detection of drug-induced antibodies have become much more sensitive, which means that target sensitivities in the low nanogram or even picogram range can now be obtained. While it is exciting to have access to such highly sensitive methods, it is important to consider if antibodies at these low concentration levels are clinically relevant, and also if the antibodies against biological drugs that are detectable prior to the initiation of the treatment have any clinical implication.
ADA Sensitivity: Identifying and Interpreting Immune Response
It is known from clinical immunology that antibodies may precede the clinical onset of immune-mediated diseases. Consequently, provided that antibodies can predict the onset of diseases, assays for the detection of antibodies cannot be too sensitive. This is important because the early detection of immune response, however slight, may enable physicians to interfere at an earlier stage of a disease’s progression, with the ultimate goal of improving patient outcomes. Seeing all drug-induced antibodies can help guide us to identify clinically meaningful data and more accurately correlate immunogenicity with clinical impact.
That said, the real challenge now lies not as much in the analysis, but in the interpretation of immunogenicity data. Over-interpretation of low antibody concentrations may exclude some patients from beneficial treatment options and under-interpretation may put patients’ safety at risk; neither extreme is an option.
Novel Biomarkers to Aid in Interpretation of ADA Data
In addition to the fact that ADA assays have grown increasingly more sensitive, novel biomarkers have become a critical tool in the interpretation of immunogenicity data. The context of use for biomarkers in drug development can range from patient stratification to assessment of safety and efficacy, and there are already a plethora of biomarkers used for diagnostic, monitoring, predictive, prognostic, safety, susceptibility, and drug response purposes. Careful and thorough data interpretation, which takes into account the clinical manifestation of clinically relevant biomarkers – including PK – is needed. In the future, response biomarkers will be used more frequently to interpret the neutralizing capacities of ADA. Others will be used for patient selection, for the identification of disease entities, and possibly also for the prediction of the risk for unwanted immune reactions.
I very much welcome any kind of technological advancements that will improve our ability to detect ADAs more sensitively and specifically, but it must be balanced with ongoing development of scientific knowledge to enable us to effectively understand the cause and clinical consequences of unwanted drug-induced immune responses when they are identified.
Join Me for an Upcoming Webinar to Learn More
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? I will be addressing this subject and others related to accurately correlating unwanted immunogenicity with clinical impact in an upcoming webinar co-hosted with Bioanalysis Zone on Wednesday 14 November 2018 at 15:00 GMT / 10:00 EST. Register here to save you spot.