Background: Shiga toxin (Stx), produced by enterohemorrhagic Escherichia coli (EHEC), is a highly potent exotoxin responsible for severe complications such as hemolytic uremic syndrome (HUS). Among its isoforms, Stx2 exhibits stronger cytotoxicity and poses greater clinical risk, yet no effective therapy currently exists. Methods: In this study, two human monoclonal antibodies, YG12-1 and YG12-2, were identified from a phage display library and systematically characterized using an integrated modeling–validation workflow. Results: Structural modeling with ImmuneBuilder and Rosetta revealed that YG12-2 possessed a longer CDRH3 topology, more short-range hydrogen bonds, and stronger electrostatic complementarity, corresponding to lower binding energy and higher apparent affinity in ELISA and SPR. Although YG12-2 had a better affinity, YG12-1 shows better protective activity in a murine model of acute peritoneal infection. This paradox highlights a non-linear relationship between structural affinity and biological efficacy, emphasizing the importance of functional epitope accessibility and pharmacokinetic behavior in determining neutralization outcomes. Conclusions: Overall, these results indicated that targeting Stx2 with YG12-1 and YG12-2 could serve as a promising protective strategy against E. coli O157:H7 infection.

As the predominant antibody isotype at human mucosal surfaces, immunoglobulin A (IgA) exerts critical functions in mucosal defense and systemic immune homeostasis. The two IgA subclasses, IgA1 and IgA2, possess distinct structural and functional features and assemble into dimeric IgA (dIgA) and secretory IgA (sIgA) under physiological conditions. With advances in cryo-electron microscopy, the molecular architecture and assembly of sIgA have been clearly characterized. While IgA protects hosts from pathogenic infection and sustains immune balance, aberrantly altered IgA contributes to the pathogenesis of IgA nephropathy and autoimmune encephalitis. To date, IgA-based therapeutics have displayed promising therapeutic efficacy against respiratory disorders, inflammatory bowel diseases and oral fungal infections. Through standardized retrieval and categorical sorting of the published literature covering IgA structure, physiological functions, disease pathogenic mechanisms and therapeutic research, this review systematically organizes relevant research advances, analyzes the bottlenecks and translational prospects of IgA-targeted therapeutics, and provides objective references to accelerate the clinical translation of IgA antibody agents.