The antigen-specific immunotherapy, AKS-107, selectively depletes anti-insulin B lymphocytes in the pancreas and reduces insulitis in T1D-prone mice 2259549

Abstract

Abstract Introduction Type 1 diabetes (T1D), results from T cell-mediated destruction of insulin-producing beta cells. Developing new immunotherapies that control islet autoimmunity without compromising protective immune responses is an important therapeutic goal. Insulin autoantibodies predict T1D in mice and humans, implicating B lymphocytes in islet attack. Anti-insulin B cells present autoantigen to T cells to promote T1D in non-obese diabetic (NOD) mice and are required for diabetes to develop. AKS-107 is an antigen-specific immunotherapy composed of a hormonally inactive insulin moiety that lacks a critical T cell epitope and which is fused to an Fc. AKS-107 specifically eliminates anti-insulin B cells and prevents diabetes in mice. However, it is unknown whether AKS-107 can deplete anti-insulin B cells in the pancreas or reduce islet inflammation. Methods VH125SD.NOD mice were treated either once or twice weekly with 0.4 mg/kg of AKS-107 for either 2 or 8 weeks. Pancreas, pancreatic lymph nodes, and spleen were harvested, and flow cytometry phenotyping was used to evaluate selective anti-insulin B cell depletion. NOD mice were treated twice weekly with 2 mg/kg of AKS-107 for 9 weeks after which pancreata were harvested, sectioned, and insulitis severity was blind scored. Results AKS-107 therapy selectively depletes anti-insulin B cells (but not other B cells) in the pancreas and pancreatic lymph nodes of VH125SD.NOD BCR transgenic mice, in which a 1-3% population of anti-insulin B cells can be readily tracked. This observed depletion is not caused by AKS-107 masking the detection of the anti-insulin B cells by biotinylated insulin. NOD mice treated with AKS-107 from 4-13 wks of age showed decreased insulitis severity relative to controls. Conclusion Our data highlight pancreas tissue actions of the antigen-specific immunotherapy, AKS-107 which supports its potential as a novel T1D immunotherapy. Funding Source This work was supported by Breakthrough T1D (formerly the Juvenile Diabetes Research Foundation) grants 3-SRA-2024-1562-S-B (RHB) and 3-PDF-2024-1495-A-N (DHM), and NIH grants F30 DK145130 (LMC), F31 DK141224 (LEB), T32 AR059039 (TWJ), and T32 GM007347 (LMC). We also acknowledge the Vanderbilt University Medical Center (VUMC) Flow Cytometry Shared Resource [supported by supported by the Vanderbilt Ingram Cancer Center (P30 CA068485) and the Vanderbilt Digestive Disease Research Center (P30 DK058404)], the VUMC Tissue Pathology Shared Resource [supported by NCI/NIH Cancer Center Support Grant, P30 CA068485], and the Islet and Pancreas Analysis Core [supported by the Vanderbilt Diabetes Research and Training Center (NIH grant P30 DK20593)]. Topic Categories Therapeutic Approaches to Autoimmunity (THER)