Structural mechanism of anti-MHC-I antibody blocking of inhibitory NK cell receptors in tumor immunity

Structural mechanism of anti-MHC-I antibody blocking of inhibitory NK cell receptors in tumor immunity | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Structural mechanism of anti-MHC-I antibody blocking of inhibitory NK cell receptors in tumor immunity David Margulies, Jiansheng Jiang, Abir Panda, Kannan Natarajan, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7133881/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Feb, 2026 Read the published version in Communications Biology → Version 1 posted You are reading this latest preprint version Abstract Anti-major histocompatibility complex class I (MHC-I) mAbs can stimulate immune responses to tumors and infections by blocking suppressive signals delivered via various immune inhibitory receptors. To understand such functions, we determined the structure of a highly cross-reactive anti-human MHC-I mAb, B1.23.2, in complex with the MHC-I molecule HLA-B*44:05 by both cryo-electron microscopy (cryo-EM) and X-ray crystallography. Structural models determined by the two methods were essentially identical revealing that B1.23.2 binds a conserved region on the 21 helix that overlaps the killer immunoglobulin-like receptor (KIR) binding site. Structural comparison to KIR/HLA complexes reveals a mechanism by which B1.23.2 blocks inhibitory receptor interactions, leading to natural killer (NK) cell activation. B1.23.2 treatment of the human KLM-1 pancreatic cancer model in humanized (NSG-IL15) mice provides evidence of suppression of tumor growth. Such anti-MHC-I mAb that block inhibitory KIR/HLA interactions may prove useful for tumor immunotherapy. Biological sciences/Structural biology/Electron microscopy/Cryoelectron microscopy Biological sciences/Immunology Full Text Additional Declarations There is NO Competing Interest. Supplementary Files 8TQ6D1000276347valreportfullP1.pdf X-ray crystal structure of Fab B1.23.2 complexed with HLA-B*44:05 9D74D1000285762valreportfullP1.pdf Cryo-EM of Fab B1.23.2 complex with HLA-B*44:05 9OA9D1000295033valreportfullP1.pdf Cryo-EM of mAb B1.23.2 Fc domain 9D73D1000285761valreportfullP1.pdf Cryo-EM of anti-MHC-I mAb B1.23.2 in complex with HLA_B*44:04 Cite Share Download PDF Status: Published Journal Publication published 02 Feb, 2026 Read the published version in Communications Biology → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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