Crystal structure of the CD33/Fab-10C8 complex elucidates the mechanism of antibody antagonism in HBV-induced immunosuppression
Dr. Hsiao, Chwan-Deng - May, 2026
This study elucidates the structural mechanism by which the monoclonal antibody 10C8 inhibits CD33 to counteract Hepatitis B virus (HBV) immune evasion. By determining the 3.2 Å crystal structure of the CD33-ECD and Fab-10C8 complex, a unique 2:2 stoichiometry that locks CD33 into a compact arrangement. This structure reveals that it sterically occludes HBsAg engagement and restricts CD33 clustering, thereby preventing downstream inhibitory signaling. Ultimately, 10C8 locks CD33 into a signaling-refractory conformation to reverse HBV-induced immunosuppression. These findings provide a structural framework for designing Siglec-targeted immunotherapies against chronic viral infections and immune disorders.
A. Canonical inhibitory signaling: In the absence of antibody, CD33 engages the α2,6-linked sialoglycan at Asn146 of HBsAg through its V-set domain. This interaction triggers ITIM phosphorylation, leading to SHP-1/2 recruitment and subsequent suppression of effector functions, including cytokine secretion, phagocytosis, and ROS production. B. Steric occlusion: mAb-10C8 binds to the CD33 V-set domain with high affinity. Although the 10C8 epitope does not directly overlap with the canonical sialic acid-binding pocket, the antibody’s lateral orientation effectively blocks HBsAg access through steric hindrance. C. Conformational locking and signaling blockade: The formation of a stable 2:2 stoichiometry complex induces a more compact dimeric arrangement of CD33. This rigid, antibody-enforced conformation restricts the conformational plasticity required for receptor clustering and efficient SHP-1/2 recruitment, thereby neutralizing HBV-induced immunosuppression and restoring myeloid cell activation.
