Data from 23ME-01473, an Fc Effector–Enhanced Anti-ULBP6/2/5 Antibody, Restores NK Cell–Mediated Antitumor Immunity through NKG2D and FcγRIIIa Activation

• DOI: 10.1158/2767-9764.c.7731426
• Publication Date: 2025-03-21T14:33:07Z
• Authors: Joel S. Benjamin; Abigail Jarret; Shashank Bharill; Pierre Fontanillas; Shruti Yadav; Debasish Sen; Dina Ayupova; Danielle Kellar; Susanne Tilk; Clifford Hom; Zahra Bahrami Diz...; I-Ling Chen; Anh N. Diep; Shi Shi; Nives Ivic; Caroline Bonnans; Alex Owyang; Pranidhi Sood; Germaine Fuh; Maike Schmidt; Kimberline Y. Ger...; Patrick Koenig; Mauro Poggio
• Keywords: NKG2D; Cell mediated immunity; Cellular immunity

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