Islet-Targeted ZnT8 Antibodies Protect Pancreatic β-Cells From Inflammatory Stress

Inflammatory stress increases endoplasmic reticulum protein-folding burden in β-cells and amplifies immunogenicity through HLA-I hyperexpression, yet targeted strategies to restore β-cell proteostasis are lacking. We demonstrate that an islet-specific, cell surface-directed antibody is internalized and functions as a zinc transporter 8-selective chaperone, enhancing endoplasmic reticulum folding capacity, attenuating HLA-I hyperexpression, and robustly inducing programmed death-ligand 1. Identification of programmed death-ligand 1 as a direct pharmacodynamic marker of zinc transporter 8-chaperoning links on-target engagement to reinforcement of local immune checkpoint signaling. Humanized Fc-silent Isle43 shows durable pancreatic retention, dose-dependent reversal of new-onset type 1 diabetes in nonobese diabetic mice, sustained remission after treatment cessation, and protection of human islet graft function in vivo. This islet-targeted strategy preserved β-cell function in inflammatory mouse models and human islet grafts, supporting an islet-targeted therapeutic approach for inflammatory β-cell failure.