September 1, 2010 (Vol. 30, No. 15)

Measuring Potential Responses Serves as Key Step in Guiding Development of Novel Drugs

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.

Edwin Merrifield, Ph.D.

Study Design

Such studies can provide valuable information concerning significant immunogenicity of biological products, including their characteristics and potential clinical consequences. They can also be valuable for preliminary comparative immunogenicity studies for biosimilar products or following production or process changes introduced for established products.

Unwanted immunogenicity, however, can occur at a level that will not be detected by such studies when conducted at a pre-approval stage, due to the restricted number of patients normally available for study.

For example, the clinically significant immunogenicity problems now widely acknowledged for erythropoietin (EPO) could not have been revealed even by the relatively large, well-planned studies that are possible to conduct at this stage. In view of this, it is usually necessary to continue assessment of unwanted immunogenicity and its clinical significance post-approval, usually as part of pharmacovigilance surveillance. 

The consequences of an immune reaction to a therapeutic protein range from the transient appearance of antibodies without any clinical significance to severe life-threatening conditions. As a rule, therapeutic proteins should be seen as individual products, and experience from related proteins can only be considered supportive.

Also in this respect, concomitant medications and other patient-related factors have to be taken into account, since these can also influence the clinical presentation of immunogenicity. Therefore, the risk of immunogenicity needs to be considered individually for each indication and patient population.

Factors that influence whether antibodies to a therapeutic protein will induce clinical consequences include the epitope recognized, affinity, and class of the antibody. Usually, antibodies recognizing epitopes on the therapeutic protein not linked to activity are associated with fewer clinical consequences. However, such antibodies can influence pharmacokinetics and, as such, influence efficacy indirectly.

Neutralizing antibodies, which interfere  with biological activity by binding to or near the active site, or by induction of conformational changes, can induce loss of efficacy. Discrimination between neutralizing and non-neutralizing antibodies is of great importance, and the assays used should be able to discriminate accordingly.

Correlation of antibody characteristics with clinical responses requires a comparison of data generated in assays assessing antibody responses with results generated using patients’ samples. Most of the latter are product-specific—e.g., assessing expansion of leukocyte populations by colony-stimulating factors increased reticulocyte numbers by erythropoietin. Such assays need to be selected according to product and need.

It might be difficult, in many cases, to identify a clinical endpoint that is sensitive enough to establish the impact on clinical outcome directly, and adoption of a surrogate measure of response may be an option.

In vivo comparison of a patient’s clinical responses to a product before and following antibody induction can provide information on the correlation between antibody development (and antibody characteristics) and clinical responses. This can be done either by intragroup analysis (i.e., response in patients before and after occurrence of antibodies) or by comparison with patients within the study who do not show an immune response.      

Testing for immunogenicity is an important component of any drug discovery program and is sure to play a key role in the development of future pharmaceuticals.

Edwin Merrifield, Ph.D. ([email protected]), is director of biomarker technical operations at Pacific Biomarkers.

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