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.