Assessment of Neutralizing Antibody Activity in Clinical Studies: Use of Surrogate Measurements Instead of Stand‑alone Assays

Neutralizing antibodies (NAbs) to protein therapeutics have traditionally been assumed to be the most impactful subset of
anti-drug-antibodies (ADA). NAbs can block the biotherapeutic from engaging its target impacting efficacy and may also
cause serious safety events. Stand-alone NAb assays have been employed to detect neutralizing responses, often with reconfigured versions of other assays. These methods have historically been implemented in registrational trials for all molecules, and
in early-stage studies for high risk biotherapeutics. However, data has demonstrated that NAb response and ADA magnitude
are highly correlated. Additionally, the use of other markers to identify clinically relevant immunogenicity, such as apparent
impact on pharmacokinetics (PK) or pharmacodynamics (PD), has been increasing. This manuscript reviews the available
data on clinically meaningful immunogenic responses to biologics and proposes a risk-based strategy to determine if and
when to employ a stand-alone NAb assay.