Immunogenicity is the ability of an individual to generate antibodies against dosed protein therapeutics. Although the above sentence plainly states ADA immunogenicity testing, the underlying process is highly complex and requires robust bioanalytical methods such as liquid chromatography-mass spectrometry to identify and characterize anti-drug antibodies. Anti-drug antibodies may induce unwanted immune responses and affect the efficacy and safety of a drug product. Therefore, regulatory authorities have stringent requirements for immunogenicity safety studies.
Anti-drug antibodies observed during preclinical and clinical studies significantly alter the efficacy, pharmacokinetics, and toxicological profiles. These effects are generally due to drug-induced autoantibodies against therapeutic protein products. Adverse ADA reactions may vary depending on the structure and function of active ingredients. The US FDA recommends a multitiered approach for anti-drug antibody assays, beginning with screening assays followed by confirmation and characterization assays. The current article focuses on ADA assay development.
The journey of ADA assays: from inception to ADA detection
The primary objective of a drug development project is to understand the ADME properties of a dosed drug product. Hence, antibody immunogenicity assays are usually an afterthought. Besides, understanding the interconnected pharmacokinetics and pharmacodynamic properties helps researchers make critical decisions during early drug development programs. While these bioanalytical tests are critical for the development of a drug product, antibody immunogenicity assays are equally critical for understanding the safety of a protein biotherapeutic.
The primary objective of immunogenicity testing depends on how and where a drug candidate is in the development life cycle. Generally, pivotal toxicological studies are the initial testing place for anti-drug antibodies. These studies include nonhumans and rodents. Although the effect an anti-drug antibody has on the pharmacokinetic parameters in animals may not necessarily correlate with human data, toxicological ADA studies help researchers understand an ADA response and prepare them to focus on eliminating ADA responses in human studies. Moreover, this animal toxicological assessment gives researchers a head start for developing ADA assays during clinical trials.
In human clinical trials, anti-drug antibody testing becomes critical. Before filing an IND, sponsors should begin a positive control or surrogate antibody generation program. The data obtained from early ADA testing not only improves our understanding of PK properties but also helps us understand the safety profile of a drug. Besides, this testing can help us understand whether an antibody response is persistent or transient. Additional tests can further improve the understanding of the safety profile of a protein therapeutic. This testing can determine the relative abundance and potentially correlate safety events with ADA prevalence.
Therefore, it is crucial for sponsors to not only understand ADA assay development concerning unique protein therapeutics but also to have an adequately designed immunogenicity testing strategy. The main focus should be on immunogenicity method development and validation, including the robust approach to determine assay cut points that exceed regulatory expectations, improving drug tolerance issues, and resolving interference from endogenous components. Moreover, drug development projects approaching critical points should have adequate measures to enable the success of biotherapeutic programs.
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