Over the past decades, the number of biotherapeutic drug products has increased. Although they provide significant advantages for patients, protein-based biotherapeutics induce unwanted immunogenicity. These unwanted immune reactions can increase the risk of adverse effects and result in the loss of drug efficacy. Understanding the importance of such complex possibilities, regulatory agencies mandate immunogenicity testing as a part of biotherapeutic drug development.
Today, several efforts are made to reduce the immunogenicity of biopharmaceutical drug products. However, drug developers still face unexpectedly high rates of immunogenicity, leading to new obstacles in assessing antibodies and their clinical relevance. These challenges need robust immunogenicity testing and have resulted in the development of reliable and sensitive anti-drug antibody ADA assays. Today advances in ADA assay development have led to the development of super-sensitive ADA antibody assays that can detect more ADAs than earlier bioanalytical assays. The current article discusses ADA analysis. However, robust ADA validation and development will remain crucial for delivering reliable results.
ADA immunogenicity testing
Since the first approval of recombinant human protein, the development of biotherapeutics has increased over time. Today, we have more than 250 biotherapeutics approved for several medical treatments.
A major difference between a large molecule and a traditional small molecule is its ability to induce unwanted immune reactions. The human body recognizes a biotherapeutic drug as a foreign invader and produces anti-drug antibodies against the drug molecule. Although advances in protein engineering have greatly reduced the primary protein sequence, the human system can still recognize the differences and may lead to secondary and tertiary structures, making them foreign to the human body. Notably, drug immunogenicity may also involve cellular immune responses. However, regulatory agencies do not require assessing cellular immunogenicity.
Almost all biotherapeutic drugs can induce immunogenicity. Particularly for therapeutic monoclonal antibodies, efforts have been made to reduce immunogenicity reactions. One example is the transition of primary and murine monoclonal antibodies to fully humanized monoclonal antibodies. Besides, advances in efforts to reduce immunogenicity incidence have further helped progress the development of biotherapeutic drug products.
Anti-drug antibodies can induce adverse reactions, such as infusion reactions, and result in the loss of efficacy. Moreover, in rare cases, ADA immune responses may also be directed to the endogenous protein counterpart of the drug molecule and induce a life-threatening outcome. Hence, it becomes crucial to determine the characteristics of a potential immunogenic response and any associated clinical consequences.
Without a robust ADA assay, developing a biologic product and acquiring regulatory approval is challenging. The success of any ADA immunogenicity testing depends on accurate and reliable ADA assays. Joint efforts from different associated parties, including developers, regulatory agencies, and academics, have resulted in the development of numerous super-sensitive assays. Such an initiative has helped drug developers detect and analyze more anti-drug antibodies.
assay development and validation will remain crucial for deciding the future of biotherapeutic drug development. Besides, any advances in bioanalytical methods and technology platforms will continue to benefit the life cycle of pharmaceutical drug products and eventually benefit a large patient population.