Rethinking immunogenicity: an integrated approach reveals the PK/PD impact of pre-existing and drug-sustaining ADA

AIMS: The traditional immunogenicity paradigm resulting in anti-drug antibody (ADA) and neutralizing antibody (NAb) positive/negative status and ambiguous or imprecise titers may overlook clinically relevant effects of ADA on pharmacokinetics (PK) and pharmacodynamics (PD). Employing risk-based strategies that integrate PK and PD analyses with ADA magnitude using signal-to-noise (S/N) can provide early insight into potential clinical impact of immunogenicity. MATERIALS AND METHODS: In a Phase 1 evaluation of DLX-2323, a humanized single-chain variable fragment (scFv) antibody that binds human IL-1β, ADA-sensitive PK and PD assays were employed to measure DLX-2323 concentration, PD activity, and assess the impact of ADA on PK and PD in healthy participants. RESULTS: The presence of pre-existing ADA was observed in one-third of participants and resulted in high variability of DLX-2323 exposure and PD activity. Pre-existing ADA magnitude correlated with a drug-sustaining impact on PK and PD, with lower clearance (CL/F) and volume of distribution (Vd/F) of DLX-2323 relative to increasing ADA signal. CONCLUSIONS: ADA effects on drug exposure and PD activity provided clinically meaningful information that standalone neutralizing antibody assays could not.