Biologist, Ph.D. National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, Maryland, United States
Disclosure(s):
Jiansheng Jiang, PhD.: No financial relationships to disclose
Introduction/Rationale: Anti-MHC-I mAbs in human and murine systems can stimulate immune responses to tumors and infections by competitively blocking inhibitory signals delivered by MHC-I-specific inhibitory receptors of several inflammatory cell types (Panda, A.K. et al. J Immunol, 2020). Previous work showed that anti-MHC-I mAbs could activate immune responses by blocking the interactions of HLA with inhibitory receptors like leukocyte immunoglobulin-like receptors LILR (Panda, A.K. et al. Cancer Immunol. Res., 2025).
Methods: Here, we determined the structure of a broadly reactive anti-human MHC-I mAb, B1.23.2, in complex with the MHC-I molecule HLA-B*44:05 by both X-ray crystallography and cryo-electron microscopy (cryo-EM) (Jiang J. et al. Commun. Biol. 2025, in review)
Results: The determined structure revealed that B1.23.2 binds to a conserved region on the MHC-I molecule that overlaps with the binding sites for killer immunoglobulin-like receptors (KIRs), indicating the binding competition between anti-MHC-I mAb and KIRs. These studies prompted experiments evaluating B1.23.2 treatment in the human KLM-1 pancreatic cancer model using humanized (NSG-IL15) mice, providing evidence of tumor growth suppression by these anti-MHC-I mAbs.
Conclusion: We proposed a mechanism of anti-MHC-I mAb blocking NK cell inhibitory receptors, which is distinct from other checkpoint mAb mechanisms. These results provide new insights into the structural basis of how anti-MHC-I antibodies can be used in cancer immunotherapy by specifically targeting inhibitory receptor interactions.
