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 α21 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.
Data availability
The cryo-EM maps were deposited in the Electron Microscopy Data Bank under the accession IDs EMD-46601 (3.02 Å), EMD-46602 (3.31 Å), and EMD-70276 (3.44 Å), and the atomic coordinates were deposited in the PDB under the accession IDs 9D73, 9D74, and 9OA9. X-ray crystal structure data and atomic coordinates were deposited in PDB under the accession ID 8TQ6. All source data for graphs, plots, and structures may be obtained from the authors. Numerical source data for plots is found in Supplementary Data 1 (for Supplementary Fig. 1b) and Supplementary Data 2 (for Figs. 1a and 3d).
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Acknowledgements
This work was supported by the Division of Intramural Research of the NIAID, NIH. X-ray data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID (or 22-BM) beamline at the Advanced Photon Source, Argonne National Laboratory. SER-CAT is supported by its member institutions (www.ser-cat.org/members.html) and equipment grants (S10_RR25528 and S10_RR028976) from the National Institutes of Health. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. The Electron Microscopy Resource is supported by the National Cancer Institute and NIH Intramural Research Program Cryo-EM Consortium (NICE). Access to the Luminex instrument was provided by Dr. Dimitri Monos (CHOP) and the CHOP Immunogenetics Laboratory.
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J.J., K.N., A.K.P., E.M.S., and D.H.M. conceived the study. J.J., K.N., H.L., J.A., Z.C.L., A.J.M., and R.K.H. collected cryo-EM data. J.J. analyzed cryo-EM data and solved structures. J.J. and K.N. collected and analyzed X-ray data. K.N., L.F.B., and R.R.T. purified protein and performed binding studies. S.S. and M.M.-S. performed molecular dynamics studies, and Y.S. and N.S. analyzed antibody specificity. S.C. and A.K.P. studied cell activation and tumorigenesis. J.J., K.N., E.M.S., and D.H.M. wrote and revised the paper.
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Jiang, J., Panda, A.K., Natarajan, K. et al. Structural mechanism of anti-MHC-I antibody blocking of inhibitory NK cell receptors in tumor immunity. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09641-8
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DOI: https://doi.org/10.1038/s42003-026-09641-8
