The Body’s Watchdog: Demystifying Immunogenicity Testing for Safe Drug Development

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Biologics for treating severe conditions such as cancer, inflammatory disease, and rheumatoid arthritis have revolutionized medicine. However, immunogenicity continues to pose significant challenges in developing effective biotherapeutics. Immunogenicity is unwanted immune responses characterized by the development of antidrug antibodies against biologics and other protein-based therapies.

Although immunogenicity and unwanted antidrug antibodies (ADA) influence drug safety and efficacy profile, it is perhaps a more severe issue in the pediatric population. Long-term immunogenicity-related issues may severely affect the immune system and result in loss of treatment response or impact the vulnerable patient population. The current article focuses on immunogenicity testing for safe drug development.

Immunogenicity analysis for developing safe and effective drug products

A significant challenge in immunogenicity ADA testing is related to the analytical methods used to assess ADA formation and its impact on immune reactions. Today, immunogenicity bioanalytical services have multiple techniques, such as ligand binding assays and LC-MS/MS systems for drug development studies. However, adequate ligand binding assay and LC-MS method validation are critical for generating reliable results.

Regulatory agencies recommend a multi-tiered approach for immunogenicity testing of biological drug products. This approach includes a primary screening assay to reduce false negatives, followed by confirmatory assays to reduce false positives. Finally, confirmed samples are then subjected to different ADA characterization assays, such as neutralizing antibody assay. 

The first and second tiers of assays are generally ligand-binding immunoassays. These assays rely on positive controls against antidrug antibodies developed in nonhuman species. These generated responses are polyclonal and vary from animal to animal. Hence, they result in differences against expected human responses. As a result, immunogenicity requires unique positive controls matching the established assay. These individualistic features of immunogenicity analysis make it difficult to compare assays between distinct biological products or even for the same product when studied using different assays. 

Drug developers generally performed immunogenicity analysis based on clinical suspicion or drug-level monitoring. Although assays are widely used for immunogenicity testing, other systems have demonstrated similar performances. For example, clinical immunogenicity analyses are conducted using different analytical platforms such as gene reporter assays, homogenous mobility shift assays, and mass spectrometry or surface plasmon resonance systems.

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Considering the expansion of protein therapies as well as associated clinical consequences against these therapeutics, the FDA issued a public guidance in 2014 for immunogenicity testing of therapeutic protein products. Severe consequences such as neutralization of biotherapeutics, cross-reacting endogenous proteins, and anaphylaxis require the development of preventive strategies. Besides, unwanted immune responses may induce other effects, such as delayed hypersensitivity responses and complement activation. 

Clinical signs of antidrug antibody responses may include fever, rash, proteinuria, hematuria, serositis, and hemolytic anemia. Generally, research shows that ADA-mediated clinical consequences to protein therapeutics determine the selection of appropriate mitigation strategies.

In Conclusion

Drug developers face obstacles while getting approval for biologics due to their associated risk factors. Hence, a collaborative approach between industry and research institutions is required to develop predictive tools and design immunogenic sequences during the early drug discovery stage. Besides, identifying methods to generate product-specific tolerance for maintaining efficacy will be critical for patient safety.

kalpana sharma

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