Do Off-Targets Resemble Intended Targets? A Quantitative Analysis of Clinical Antibody Specificity

Antibodies can selectively bind unintended antigens, but whether and how frequently these off-targets resemble their intended targets remains unclear. We analyzed 130 REAP-detected off-target interactions involving 45 clinical-stage or approved antibodies, comparing sequence, global structure, and local epitope similarity against same-assay nonhits. Off-targets showed no consistent enrichment in sequence, structure, or surface resemblance. Local epitope searches likewise showed no robust distinction, although structural and surface coverage and sensitivity limited interpretation. These findings suggest that homology alone is insufficient to anticipate antibody off-target recognition, motivating antigen-resolved screening and improved interaction-level prediction methods