Immunogenicity assessment in biosimilar development spans analytically distinct questions. Molecular or product differences may create theoretical immunogenicity concerns, anti-drug antibody assays detect immune responses under method-dependent conditions, and only a subset of detected responses has demonstrable pharmacokinetic, pharmacodynamic, efficacy, or safety consequences. Treating these observations as interchangeable can exaggerate the significance of analytical differences or antibody positivity. This scoping review maps how biosimilar immunogenicity evidence moves across product characteristics, patient and treatment conditions, assay and sampling design, anti-drug antibody characteristics, clinical consequences, and switching contexts, with emphasis on the boundaries between observation and clinically relevant inference. Peer-reviewed literature published from 2017 through 2024 was scoped using a Population–Concept–Context framework. Evidence was charted according to product and analytical attributes, population and treatment context, immunogenicity-assay characteristics, antibody phenotype, pharmacological consequences, clinical outcomes, and switching exposure. Evidence derived from analytical characterization, comparative clinical studies, methodological scholarship, and broader immunogenicity or switching syntheses was retained in analytically distinct categories. The mapped evidence indicates that biosimilar immunogenicity cannot be interpreted from a single evidentiary layer. Analytical differences require functional and risk-context interpretation; anti-drug antibody incidence is sensitive to assay and sampling conditions; antibody positivity does not necessarily imply neutralization or altered exposure; and clinically relevant immunogenicity depends on convergence with pharmacological, efficacy, or safety evidence. Patient state, treatment history, concomitant therapy, repeated exposure, and expectations surrounding switching can further alter the interpretation of observed outcomes. Immunogenicity assessment is best treated as a bounded inference problem rather than a linear progression from molecular difference to clinical harm. The review supports separation of product-level concern, measured immune response, functional consequence, and clinical relevance while identifying the evidence required to justify movement between these levels.
IJPRAS
