Assay Signal as an Alternative to Titer for Assessment of Magnitude of an Antidrug Antibody Response

Abstract

Background: Titer methods are commonly used to characterize the magnitude of an antidrug antibody response. Assay S/N is an appealing alternative, but the circumstances under which use of signal-to-noise (S/N) is appropriate have not been well defined. Results: We validated both titer and S/N-based methods for several therapeutics. S/N correlated strongly with titer both in aggregate and when examined on a per subject basis. Analysis of impact of antibody magnitude on pharmacokinetics yielded the same result using either method. Each assay demonstrated excellent precision, good linearity, and adequate drug tolerance. Conclusion: Under these circumstances, assay S/N is a valid alternative to titer for assessment of the magnitude of an antidrug antibody response.

Immunogenicity of erenumab: A pooled analysis of six placebo-controlled trials with long-term extensions

“…The magnitude of the ADA response, characterized using the S/N value from binding ADA-positive samples as an alternative to titer (17), was low in the majority of anti-erenumab binding antibody-positive patients (Figure 2). Of the 188 anti-erenumab binding antibody-positive patients (185 developing and 3 pre-existing) from the global studies, 80.3% (151/188, including the 3 pre-existing antibody-positive patients) had a maximum S/N ratio (S/N max ) ≤ 5 and 93.6% (176/188) ≤ 20 (Figure 2).…”

“…Anti-erenumab binding antibodies were detected using a validated electrochemiluminescence (ECL)-based bridging immunoassay on the Meso Scale Discovery (MSD) platform and followed a two-tiered assay approach (screening and specificity) with an assay sensitivity of 24.73 ng/mL (specificity assay) and drug tolerance (specificity assay) of 100 μg/mL or 10 μg/mL erenumab at an anti-erenumab antibody concentration of 500 ng/mL or 100 ng/mL, respectively. The assay met criteria for the use of signal-to-noise (S/N) values as an alternative to titer for characterization of the magnitude of the ADA response (17). The screening assay was performed on serum samples to detect the presence of binding antibodies to erenumab, using biotinylated and ruthenylated erenumab as capture and detection reagents, respectively.…”