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

Area of Science:

• Immunology
• Endocrinology
• Cell Biology

Background:

• Inflammatory stress impairs beta-cell function by increasing endoplasmic reticulum protein-folding burden and HLA-I hyperexpression.
• Current therapeutic strategies lack targeted approaches to restore beta-cell proteostasis.

Purpose of the Study:

• To investigate an islet-specific antibody as a potential therapeutic for inflammatory beta-cell failure.
• To evaluate the antibody's ability to restore beta-cell proteostasis and modulate immune responses.

Main Methods:

• Development of an islet-specific, cell surface-directed antibody (Isle43) engineered for Fc-silence.
• Assessment of antibody internalization, zinc transporter 8-selective chaperoning activity, and effects on endoplasmic reticulum folding capacity and HLA-I expression.
• Evaluation of programmed death-ligand 1 induction as a pharmacodynamic marker.
• In vivo studies using nonobese diabetic mice and human islet grafts to assess therapeutic efficacy and graft protection.

Main Results:

• The antibody functions as a zinc transporter 8-selective chaperone, enhancing endoplasmic reticulum folding capacity and reducing HLA-I hyperexpression.
• Programmed death-ligand 1 was identified as a direct pharmacodynamic marker of antibody engagement, reinforcing local immune checkpoint signaling.
• Humanized Fc-silent Isle43 demonstrated durable pancreatic retention and dose-dependent reversal of type 1 diabetes in mice, with sustained remission.
• The antibody protected human islet graft function in vivo and preserved beta-cell function in inflammatory models.

Conclusions:

• Islet-targeted chaperoning by Isle43 restores beta-cell proteostasis and function in inflammatory settings.
• This strategy effectively reverses and maintains remission of type 1 diabetes in preclinical models.
• Isle43 represents a promising therapeutic approach for inflammatory beta-cell failure and autoimmune diabetes.