Drug-induced immunogenicity is a significant challenge for biological drugs. Biological drugs such as antibodies, proteins, and peptides are large and complex structures. These complex drug products induce innate immune responses in patients leading to anti-drug antibodies (ADA) formation. ADA can inactivate the pharmaceutical drug, affect its targeting ability, and increase the clearance of ADA drug complexes. This inactivation may affect its efficacy and may lead to sub-optimal exposure. Besides, ADA formation in patients leads to increased toxicity associated with immune responses and ADA formation, affecting data generated from PK and PD studies in clinical trials.
ADA Immunogenicity testing services employ various bioanalytical methods, such as ELISA ADA assay, ADA antibody assay, and ADA titer assay. Different medical studies have demonstrated the importance of ADA formation in therapeutic intervention. However, the risk and consequences of ADA formation in oncology may differ from other fields, such as rheumatology and hematology. ADA formation in oncology needs specific consideration, such as using immunostimulatory compounds, concomitant treatment, immunosuppressing therapies, and understanding the nature and features of immunocompromised patients. Therefore, the current article explores the opportunities and challenges of ADA formation in immuno-oncology.
Opportunities and Challenges
Understanding the impact of ADA formation on the pharmacogenomics, efficacy, and toxicity of a biological drug product is crucial to evaluating the clinical relevance of ADA formation. However, most oncology agents do not have a well-established clinical relevance to ADA formation. Some clinical data may summarize the percentage of ADA-positive patients, but the consequences of ADA formation are not investigated extensively.
Also Read: PK/PD Analysis for Biologics: Unique Considerations and Approaches
The primary approach for reducing ADA formation is to reduce the intrinsic immunogenicity of the biological drug product. However, clinical studies have shown that this approach is inadequate in reducing ADA formation in all patients. Inducing tolerance by adaptations to the treatment regimen is a prevention strategy applied in clinical practice. Let us understand this strategy in brief.
Several studies have focused on reducing immunogenicity by increasing exposure through high-frequency and high-dose therapy. However, the effects of such modifications in oncology show conflicting data. The main limitation of this specific treatment is the toxic and therapeutic effects of a biological drug. One way to avoid this limitation is to administer only the immunogenic component of the drug molecule without its active moiety. In this way, one may administer high doses of the biological drug without inducing unacceptable toxicity. Studies have shown that this approach can reduce ADA formation from 74% to 21%. However, a limitation of the strategy is that it can be very costly and time intensive.
Conclusion
Heterogeneity in immunogenicity assays and inconsistent reporting complicate the interpretation of data generated from ADA clinical trials. Consistent reporting of the incidence characteristics and assessment of detected ADA will facilitate interpreting and comparing ADA immunogenicity formation.
Moreover, immunogenicity testing services can design and execute strategies for managing and preventing ADA responses once ADAs are clinically relevant to a specific agent. One way to effectively navigate is regiment adjustment. Although this method has yet to be fully understood, studies have demonstrated clinically relevant effects.
