Biopharmaceuticals can potentially elicit an immune response in treated patients. This unwanted immune reaction may influence the safety and efficacy profile of these biopharmaceutical drug products. Hence, immunogenicity assessments are critical throughout different drug development phases, including post-marketing evaluations. Although regulatory agencies require rigorous immunogenicity assessment for biopharmaceutical drug products, there is a lack of standards for guiding research design for immunogenicity assessment or criteria to assess biopharmaceuticals.
Substantial technological advancements in bioanalytical techniques assessing immune responses have resulted in increased immunogenicity rates. However, this higher immunogenicity rate has limited the comparison of immunogenicity assessments outside clinical trials. Hence, regulatory agencies and drug developers should keep pace with evolving immunogenicity requirements. This article reviews the importance of immunogenicity assessment in biopharmaceutical drug development.
Immunogenicity testing for biopharmaceutical products
Biopharmaceuticals are developed using a living organism, often genetically engineered using plant, animal, or bacterial cells. Biopharmaceuticals are crucial in advancing patient care by offering highly targeted and effective therapeutics for several chronic and life-threatening conditions such as solid tumors, arthritis, hematology, and inflammatory bowel diseases. Compared to small molecule drug products, biopharmaceuticals are large and highly complex. Hence, they need an extended production period and highly specialized techniques.
Biopharmaceuticals, including biosimilars, may illicit unwanted immunogenicity and impact the safety and efficacy of the drug product. Researchers characterize immunogenicity by conducting antidrug antibody testing to detect them in animals or humans after biopharmaceutical administration. Antidrug antibodies (ADA) that bind to a biopharmaceutical inhibit its activity. These antibodies are called neutralizing antibodies, which bind to the active site of the drug product. Non-neutralizing antibodies do not attach to the active sites but may still be clinically crucial as they may reduce efficacy by impacting bioavailability. Antidrug antibodies are linked increasingly with reduced drug efficacy or failure to induce desired therapeutic responses.
Antidrug antibodies may impact biopharmaceuticals by altering drug pharmacokinetics or binding to the active sites, thus reducing their activity. Hence, ADA analysis is becoming crucial for biopharmaceutical drug development. ADA studies are critical, particularly during clinical trials, as unwanted immune reactions observed during ADA analysis in clinical trials may impact the safety of study subjects. Besides, ADA clinical trials should adhere to good laboratory practices.
Antidrug antibodies are associated with risks ranging from mild reactions to life-threatening outcomes. The presence of antidrug antibodies following biopharmaceutical administration does not necessarily relate to clinically meaningful outcomes on safety or efficacy. In fact, immunogenicity adverse events are relatively uncommon. However, neutralizing antibodies has the potential of cross-reacting with endogenous components, and hence unwanted immunogenicity may have profound implications for developing biopharmaceutical products.
The regulatory pathway for biopharmaceutical approval is distinct from generic small molecule drugs. The US FDA and other regulatory agencies have stringent requirements for immunogenicity assessment. Although the extent and nature of supporting immunogenicity data differ among regulatory agencies, the final approval depends on the totality of experimental evidence. However, the regulatory recommendations are critical for biopharmaceutical approval and instilling confidence in the safety and efficacy data of immunogenicity assessments.
