Biopharmaceutical products or biologics are active drug compounds produced by living cells or obtained from organisms such as yeast, bacteria, animal, or human cell lines. On the other hand, biosimilars are generic versions of an originator biopharmaceutical product produced once its patent and exclusivity have expired. Today, a global need for affordable healthcare has driven an increase in the biosimilar market.
Unlike conventional generic drugs, biosimilars face multiple challenges. Biologics are more complicated than small-molecule drugs. The complex 3D biological structure depends on the production process, such as purification, fermentation, production, formulation, packaging, and storage. Any minor variation in these processes may potentially induce variability in the macromolecular structure of biologics. These variations may have damaging implications, such as adverse events and undesirable immune responses. Hence, immunogenicity testing is a crucial component of biologics and biosimilar drug development. The current article discusses immunogenicity assays for biologics and biosimilars.
Anti-drug antibody testing for biologics and biosimilars
Unwanted immune responses to biologics and biosimilars can affect drug pharmacokinetics, pharmacodynamics, efficacy, and safety. The impact of these undesired immune responses is highly variable and may range from minor clinical effects to extremely detrimental outcomes. Measuring anti-drug antibodies is a vital tool in understanding unwanted immune responses. ADA assays can help understand the impact of anti-drug antibodies on the pharmacokinetics, pharmacodynamics, efficacy, and safety properties. This information should be included in the adverse reaction section of drug labels. Hence, selective, specific, sensitive, and valid ADA antibody assays are critical to measure anti-drug antibody responses of biologics and biosimilars.
Unlike biosimilar PK assays, biosimilar and biologic immunogenicity ADA testing involves two approaches: one assay and two assays. One assay approach includes a set of labeled drug reagents to detect both originator anti-drug antibodies and biosimilars. On the other hand, two assay approaches involve a set of labeled drug reagents to detect respective anti-drug antibodies. As immunogenicity ADA assays are not quantitative, demonstrating equivalency through qualitative testing faces additional challenges.
Two-assay ADA testing requires different assay characteristics, such as confirmatory cut point and assay component for each assay. This additional requirement makes data interpretation from future studies challenging. On the other hand, one essay approach with one set of labeled drug reagents may not fully detect other anti-drug antibodies. However, this approach allows optimum detection of biosimilar anti-drug antibodies. If the biosimilar section of comparability studies demonstrates less or equal immunogenicity than the originator drug, the regulatory requirement needs the biosimilar drug to be less or equally immunogenic than the originator. Additionally, the biggest benefit of using one assay method is that it does not present inter-assay variability introduced with the two-assay approach.
Originator ADA-positive controls are polyclonal antibodies produced by hyperimmunized animals. Hence, assessing equivalency between originator ADA positive control and biosimilar to demonstrate drug tolerance and assay sensitivity is another challenge. Besides, these ADA assays are qualitative and are more variable, especially at the LOD detection range. In conclusion, immunogenicity testing for biologics and biosimilars has unique challenges requiring adequate measures and solutions.
