Immunogenicity of Adalimumab in Bacterial Molecular Mimicry: In Silico Analysis

Background: Adalimumab, a monoclonal antibody targeting tumor necrosis factor α, treats autoimmune diseases but induces antidrug antibodies in 30% to 60% of patients, reducing its efficacy. Objective: This study aims to investigate molecular mimicry as a mechanism behind this immunogenicity, where bacterial immunoglobulin domains structurally resemble adalimumab’s light chain, triggering immune responses. Methods: Using PSI-BLASTp (National Center for Biotechnology Information) and PRALINE (Center for Integrative Bioinformatics), there are 40 bacterial antigens homologous to adalimumab, with 8 clinically relevant strains. Results: Structural analysis revealed 94% amino acid identity between the immunoglobulin domain of Escherichia coli strain B1 and adalimumab’s light chain, and 89.67% similarity with Corynebacterium pyruviciproducens. Root mean square deviation values confirmed strong structural homology. Additionally, 5 cross-reactive B-cell epitopes were predicted, suggesting overlapping surfaces that may promote immune cross-reactivity and antidrug antibody development. Conclusions: This study represents a first step toward identifying a potential microbial factor driving antiadalimumab antibody formation. The predicted cross-reactive regions provide specific candidates for further in vitro validation to confirm molecular mimicry and refine epitope mapping. Understanding these mechanisms may ultimately inform the design of less immunogenic biologics and guide clinical strategies to predict and prevent antidrug antibody formation.