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Soluble Antigen Array Displaying Proinsulin(F25D) Selectively Targets Anti-insulin B Cells without Hormonal Effects
Grant M Downes1, Kyle D Apley2, Gang Hu3
1Bioengineering Graduate Program, University of Kansas, Lawrence, Kansas 66045, United States.
Molecular Pharmaceutics
|January 23, 2026
Summary
A novel soluble antigen array (SAgA) targeting mutated proinsulin (M-PI(F25D)) shows promise for Type 1 diabetes (T1D) antigen-specific immunotherapy (ASIT). This approach avoids glycemic effects while specifically targeting autoreactive B cells and anti-insulin antibodies.
Area of Science:
- Immunology
- Endocrinology
- Biotechnology
Background:
- Type 1 diabetes (T1D) pathogenesis involves antigen presentation to autoreactive T cells by dendritic cells and B lymphocytes in pancreatic islets.
- Current immunosuppressive therapies like rituximab and teplizumab carry risks of infection due to B or T cell depletion.
- Antigen-specific immunotherapy (ASIT) offers a targeted approach to suppress or delete autoreactive cells.
Purpose of the Study:
- To develop a novel soluble antigen array (SAgA) platform for T1D intervention.
- To create a mutated proinsulin antigen (proinsulin(F25D)) conjugated to a hyaluronic acid (HA) backbone (SAgAM-PI(F25D)) that retains disease-targeting capabilities without glycemic activity.
- To evaluate the specificity and efficacy of SAgAM-PI(F25D) in targeting autoreactive B cells and anti-insulin antibodies.
Main Methods:
- Conjugation of mutated proinsulin (proinsulin(F25D)) to a hyaluronic acid (HA) backbone to form SAgAM-PI(F25D).
- Assessment of insulin receptor-β activity and in vivo glycemic effects.
- Binding assays with a disease-relevant monoclonal anti-insulin antibody and murine transgenic (Tg125) B cells specific for human insulin.
Main Results:
- SAgAM-PI(F25D) demonstrated a pronounced reduction in insulin receptor-β activity.
- The developed SAgA lacked significant glycemic activity in vivo.
- SAgAM-PI(F25D) exhibited low nanomolar binding affinity for a disease-relevant monoclonal anti-insulin antibody and bound specifically to murine transgenic (Tg125) B cells.
Conclusions:
- The mutated proinsulin SAgA (SAgAM-PI(F25D)) effectively avoids glycemic effects while maintaining specificity for anti-insulin antibodies and insulin-binding B cells.
- This SAgA platform represents a promising candidate for antigen-specific immunotherapy in Type 1 diabetes.
- The targeted approach of SAgAM-PI(F25D) offers a potential alternative to broader immunosuppressive therapies for T1D.
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