Challenging Current Immunogenicity Assessment: Clinical Case Studies for 1-Tiered Approach

Immunogenicity assessment has been evolving to incorporate sophisticated tools for risk assessments in early drug development and to develop highly sensitive ADA assays. Hence, the need for a complicated and resource-intensive 3-tiered testing approach (screening Tier-1, confirmation Tier-2 & titration Tier-3) has recently been questioned. To investigate whether a simplified 1-tiered strategy (i.e., screening Tier-1 only) would generate comparable results, we re-processed ADA data from clinical studies of three monoclonal antibody (mAb) drugs. To evaluate the necessity of Tier-2 and Tier-3 for immunogenicity assessment, correlation analysis of Tier-1 with Tier-2 and Tier-3 was performed in each study using ADA positive samples. Strong (r>0.8) correlation between Tier-1 and Tier-2 and strong to moderate (r> 0.6) between Tier-1 and Tier-3 were observed in these studies. When re-processing ADA data from each study using 1-tiered assessment with 1% false positive cut point, most samples (97%) from all three studies were reported identically (negative or positive) using either a 1-tiered or 3-tiered approach. At a patient level, 95% of patients from the studies had the same ADA response category (pre-existing, treatment-emergent [TE], and treatment-boosted [TB]) with either testing strategy. Even though 5% of patients were re-classified to a different ADA category, these patients typically had low titer ADA response with no potential clinical impact on PK, efficacy and safety. Importantly, TE ADA incidences from the 1-tiered approach were comparable with that from the 3-tiered approach for these studies. The results demonstrate that the 1-tiered testing strategy is feasible for ADA assessment of low immunogenicity risk mAb drugs while increasing the speed of data delivery, reducing cost and resource burden, and allowing regulated bioanalytical laboratories to focus on other important assessments of clinical response.