Immunogenicity is a measure of the immune response to a biotherapeutic drug. It is a very relevant issue affecting not only the use of therapeutic protein drugs such as mAbs but also peptides, enzymes, cytokines, growth factors, recombinant proteins, and other biological products.
The development of antidrug antibodies can cause allergic or anaphylactic reactions, reduction of efficacy, and/or the induction of autoimmunity. In the wake of such effects being observed in the clinical trials of earlier protein therapies, the FDA and responsible companies are insisting that immunogenicity testing become an integral part of antibody and biological drug development.
During the next decade, biopharmaceutical companies hope to introduce a new generation of antibody and biologic drugs that are safer and more effective. Many members of this new category are fragments of antibodies that can reach targets that whole antibodies cannot. Some are proving useful for treating diseases once thought to be beyond the reach of antibodies.
Clinical consequences of immunogenicity include altered clearance and assay interference for pharmacokinetics. Factors contributing to immunogenicity include the genotype of the patient, therapeutic protein sequences, uptake by immune cells, and modification in formulation. Other factors that contribute include pre- and co-medications, the route of administration, formulation, dose, and frequency of dosing.
Most biologics elicit some level of antibody response. Since this antibody response could lead to potentially serious side effects, it is necessary not only to screen for immunogenicity but also to quantify and characterize the antibody response. Recommendations have been published for the development of anti-drug antibody (ADA) immunoassays intended for clinical studies.
Many ADA tests are performed by enzyme-linked immunosorbent assay (ELISA), but electrochemiluminescence (ECL) has several advantages and so is increasingly being used for this application.
Compared to ELISA, advantages of ECL include better free drug tolerance, detection of low-affinity antibodies, higher throughput, improved sensitivity, increased dynamic range, and higher binding capacity.
Although immunogenicity is a clear concern with monoclonal antibodies, it may be an even more important issue with certain biological therapies that are not monoclonal antibodies. ADAs to proteins that are endogenous in the body offer the potential for causing severe side effects. It can be expected that higher-risk emerging therapies will be evaluated for immunogenicity more frequently than lower-risk therapies.
Supporting outsourced clinical development services for biotherapeutics requires unique capabilities and expertise. This is due to the fact that clinical development and regulatory approval are complex processes. There is often a reluctance to outsource because of the extraordinarily complex nature of these quasi-quantitative immunoassays and because guidelines by regulatory agencies are constantly evolving.
Immunogenicity studies need to be carefully and prospectively designed to ensure all essential procedures are in place before commencement. This includes the selection, assessment, characterization, and validation of all assays; the identification of appropriate sampling points, sample volumes and sample processing/storage; and selection of statistical methods for analysis of data.
This applies to assays used to measure and characterize antibodies and to methods employed for assessing clinical responses to antibodies if they are induced. Much of this needs to be established on a case-by-case basis, taking account of product, patients, and expected clinical parameters.