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This interaction induces ITIM phosphorylation and SHP-1\/2 recruitment, dampening myeloid cell activation. The monoclonal antibody 10C8 has been identified as a potent antagonist of CD33, but the structural basis for its inhibitory activity remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We determined the 3.2\u00a0\u00c5 crystal structure of the human CD33 extracellular domain (CD33-ECD) in complex with the Fab fragment of 10C8 (Fab-10C8). The stoichiometry and assembly of the complex in solution were validated by size-exclusion chromatography and analytical ultracentrifugation (AUC). Structural comparisons with apo CD33 were performed to assess potential Fab-induced conformational changes, and buried surface area analyses were conducted to characterize binding interfaces.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The structure reveals a 2:2 stoichiometry complex comprising two CD33-ECD molecules and two Fab-10C8 fragments, consistent with the 157\u00a0kDa molecular mass determined by AUC. Each Fab engages the V-set domain through extensive complementarity-determining region (CDR) interactions, burying ~612\u00a0\u00c5\n                      <jats:sup>2<\/jats:sup>\n                      of surface area, while inter-Fab contacts stabilize a compact dimeric arrangement of CD33-ECD. This geometry differs markedly from the relaxed apo state, showing a ~21\u00b0 reduction in the dimer angle. The antibody-binding epitope is adjacent to, but not overlapping with, the canonical sialic acid-binding cleft, leading to steric occlusion that prevents HBsAg engagement. Together with a potential Fab-induced ectodomain compaction, this conformation restricts CD33 clustering and likely precludes SHP-1\/2 recruitment, providing a mechanistic explanation for the antagonistic activity of 10C8.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides the structural insight into antibody-mediated inhibition of CD33. By locking CD33 into a sterically occluded, signaling-refractory conformation, 10C8 effectively reverses HBV-induced immunosuppression, thereby restoring host antiviral activity. These findings establish a structural framework for rational design of Siglec-targeted immunotherapies against chronic viral infections and other immune regulatory disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12929-026-01248-9","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T08:50:48Z","timestamp":1780044648000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Crystal structure of the CD33\/Fab-10C8 complex elucidates the mechanism of antibody antagonism in HBV-induced immunosuppression"],"prefix":"10.1186","volume":"33","author":[{"given":"Yi-Hung","family":"Yeh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Guan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Shan","family":"Sung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shie-Liang","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chwan-Deng","family":"Hsiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"issue":"3","key":"1248_CR1","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/nri1573","volume":"5","author":"B Rehermann","year":"2005","unstructured":"Rehermann B, Nascimbeni M. 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