Advancing beyond stand-alone NAb assays: perspectives and regulatory impact of applying integrated immunogenicity assessment in drug development.

Neutralizing antibody (NAb) activity assessment is a regulatory expectation in the clinical development of therapeutic proteins, traditionally addressed through standalone NAb assays. However, evolving regulatory guidance and industry experience increasingly recognize that integrated analyses of anti-drug antibodies (ADA), pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety may provide a more clinically meaningful evaluation of neutralizing activity. This perspective examines the scientific and regulatory rationale for moving beyond routine reliance on standalone NAb assays and describes a risk-based, integrated immunogenicity assessment framework. Two case studies involving low-risk monoclonal antibodies-garadacimab and clazakizumab-are presented, in which validated standalone NAb assays were available but not relied upon for primary clinical interpretation due to limited sensitivity and lack of added clinical value. Instead, longitudinal ADA characterization integrated with PK and PD or efficacy data was used to assess clinically meaningful neutralizing activity. In both cases, this approach enabled clear differentiation between detectable but clinically irrelevant immunogenicity and immunogenicity with clinical consequence and was accepted by regulatory authorities. These examples illustrate how integrated immunogenicity assessments can replace standalone NAb assays while remaining scientifically rigorous, clinically informative, and aligned with regulatory expectations.