Challenging the Standard Immunogenicity Assessment Approach: 1-Tiered ADA Testing Strategy in Clinical Trials

Area of Science:

• Biopharmaceutical development
• Immunogenicity assessment
• Assay methodology

Background:

• The established anti-drug antibody (ADA) testing strategy for protein therapeutics is nearly two decades old, developed when assay technology was basic and immunogenicity concerns were rising.
• The current resource-intensive, multi-tiered ADA testing approach uses stringent cut points to minimize false negatives, reflecting a conservative stance.
• Advancements in sensitive ADA assay platforms and the development of humanized monoclonal antibody (mAb) drugs necessitate re-evaluating the traditional testing paradigm.

Purpose of the Study:

• To explore the feasibility of a simplified one-tiered ADA testing strategy compared to the traditional three-tiered approach.
• To assess the impact of a simplified ADA testing strategy on data quality and clinical interpretation.
• To evaluate the potential for expedited data delivery and reduced resource needs in biopharmaceutical clinical development.

Main Methods:

• Re-assessment of ADA data from clinical studies involving three different mAb programs.
• Comparison of a simplified one-tiered ADA testing strategy (1% false positive cut point) against the traditional three-tiered approach.
• Analysis of correlations between screening, confirmation, and titer results, and subject-level ADA categorization.

Main Results:

• Moderate to strong correlations were observed between screening (signal-to-noise) and confirmation/titer results.
• Approximately 97% of samples and over 92% of subjects maintained the same ADA classification under both testing strategies.
• Re-categorized subjects exhibited low-titer ADA responses with no clinical impact on pharmacokinetics, efficacy, or safety.

Conclusions:

• The one-tiered ADA testing strategy is suitable for assessing antibody therapeutics in the studied programs and is likely broadly applicable.
• This simplified approach can expedite data delivery and reduce resource requirements during clinical development.
• The one-tiered strategy maintains data quality and clinical interpretability, offering a more efficient alternative to traditional multi-tiered testing.