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. 2024 Dec 12;27(1):11.
doi: 10.1208/s12248-024-00993-9.

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

Ching-Ha Lai  1 , Mu Chen  2 , Sasha Fraser  2 , Jessica Wang  2 , Sean McAfee  2 , Emma Speaks  2 , Nicholas Simeone  2 , Jacqueline Rodriguez  2 , Colin Stefan  2 , Lisa DeStefano  2 , Chinnasamy Elango  2 , Matthew D Andisik  2 , Giane Sumner  2 , An Zhao  2 , Susan C Irvin  2 , Albert Torri  2 , Michael A Partridge  2
Affiliations

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

Ching-Ha Lai et al. AAPS J. .

Abstract

The ADA testing strategy for protein therapeutics was established almost two decades ago when assay methodologies were rudimentary, and serious immunogenicity-related safety issues had recently been observed with some biotherapeutics. The current testing paradigm employs multiple tiers and stringent cut points to minimize false negatives, reflecting a conservative stance towards ADA analysis. The development of highly sensitive ADA assay platforms and technologies such as humanized or fully human monoclonal antibody (mAb) drugs has put the traditional, resource-intensive 3-tiered testing approach under scrutiny. ADA data from clinical studies for three different mAb programs were re-assessed to explore the feasibility of a simplified 1-tiered ADA testing strategy with a 1% false positive cut point versus the traditional 3-tiered approach. The analysis demonstrated moderate to strong correlations between screening results (signal-to-noise, S/N) and those of confirmation and titer results, with the vast majority of samples (~ 97%) across all studies having the same ADA positive/negative classification with either testing approach. Furthermore, at the subject level, over 92% had the same ADA category (pre-existing, treatment-emergent, treatment-boosted) under both testing approaches. The re-categorized subjects had low titer ADA responses with no observed clinical implications on pharmacokinetics, efficacy, or safety. Finally, the treatment-emergent ADA incidences were comparable between the 1-tiered and 3-tiered approaches. The results demonstrate that the 1-tiered testing strategy is suitable for ADA assessment in these programs and is likely more widely applicable. Additionally, the 1-tiered approach could expedite data delivery and reduce resource needs in clinical development without compromising data quality or clinical interpretation.

Keywords: ADA incidence; ADA testing approach; Anti-drug antibodies (ADA); Immunogenicity.

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Conflict of interest statement

Declarations. Conflict of Interest: All authors are employees of Regeneron Pharmaceuticals, Inc., and may hold stock and/or stock options in the company. Disclosure: The views expressed in this article are those of the authors and do not reflect the official policy of Regeneron Pharmaceuticals.

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