8RWB

Crystal structure of ULBP6 in complex with a blocking antibody

Summary for 8RWB

• Entry DOI: 10.2210/pdb8rwb/pdb
• Descriptor: UL16-binding protein 6, Heavy chain, Light chain, ... (8 entities in total)
• Functional Keywords: fab, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 66627.43

Authors

Bharill, S.,Chen, I.,Ivic, N.,Bahrami Dizicheh, Z.,Wu, Y.,Doamekpor, S.,Koenig, P.,Fuh, G. (deposition date: 2024-02-02, release date: 2025-02-12, Last modification date: 2025-05-07)

Primary citation

Benjamin, J.S.,Jarret, A.,Bharill, S.,Fontanillas, P.,Yadav, S.,Sen, D.,Ayupova, D.,Kellar, D.,Tilk, S.,Hom, C.,Bahrami Dizicheh, Z.,Chen, I.L.,Diep, A.N.,Shi, S.,Ivic, N.,Bonnans, C.,Owyang, A.,Sood, P.,Fuh, G.,Schmidt, M.,Gerrick, K.Y.,Koenig, P.,Poggio, M.
23ME-01473, an Fc Effector-Enhanced Anti-ULBP6/2/5 Antibody, Restores NK Cell-Mediated Antitumor Immunity through NKG2D and Fc gamma RIIIa Activation.
Cancer Res Commun, 5:476-495, 2025

PubMed Abstract: The landscape of cancer treatment has been transformed by immune checkpoint inhibitors; however, the failure to benefit a large number of patients with cancer has underlined the need to identify promising targets for more effective interventions. In this study, we leverage 23andMe, Inc.’s large-scale human germline genetic and health database to uncover the previously unknown role of UL16-binding protein 6 (ULBP6), a high-affinity NK group 2D (NKG2D) ligand, in cancer and its promise as an immuno-oncology therapeutic target. We confirm ULBP6 expression in human tumors and demonstrate that soluble ULBP6 shed from tumors circumvents NKG2D activation provided by membrane-anchored NKG2D ligands to inhibit immune cell activation and tumor cell killing. Based on these findings, we developed 23ME-01473, a humanized Fc effector–enhanced antibody that binds to ULBP6 and its closely related family members, ULBP2 and ULBP5. 23ME-01473 effectively blocks soluble ULBP6-mediated immunosuppression to restore the NKG2D axis on NK and T cells to elicit tumor growth control. Moreover, the Fc effector–enhanced design of 23ME-01473 increases its binding affinity to fragment crystallizable gamma receptor IIIa, which, together with 23ME-01473’s binding to membrane-anchored ULBP6/2/5 on cancer cells, allows for augmented antibody-dependent cellular cytotoxicity induction, providing a second activation node for NK cells. Our studies demonstrate the therapeutic potential of an Fc effector–enhanced anti-ULBP6/2/5 antibody to reinvigorate NK cell and T-cell activation and cytotoxicity for the treatment of cancer.

PubMed: 40116579
DOI: 10.1158/2767-9764.CRC-24-0478

Experimental method

X-RAY DIFFRACTION (2.307 Å)