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An antigen-specific immunotherapeutic, AKS-107, deletes insulin-specific B cells and prevents murine autoimmune diabetes

2024; Frontiers Media; Volume: 15; Linguagem: Inglês

10.3389/fimmu.2024.1367514

1664-3224

David G. Alleva, Andrea R. Delpero, Thillainaygam Sathiyaseelan, Sylaja Murikipudi, T. Lancaster, Mark A. Atkinson, Clive Wasserfall, Liping Yu, Ramya Ragupathy, Rachel H. Bonami, Todd C. Zion,

Diabetes Management and Research

Introduction The antigen-presenting cell function of insulin-reactive B cells promotes type 1 diabetes (T1D) in non-obese diabetic (NOD) mice by stimulating pathogenic T cells leading to destruction of insulin-producing β-cells of pancreatic islets. Methods/Results To target insulin-reactive B cells, AKS-107, a human IgG1 Fc molecule fused with human insulin A and B chains, was engineered to retain conformational insulin epitopes that bound mouse and human B cell receptors but prevented binding to the insulin metabolic receptor. AKS-107 Fc-mediated deletion of insulin-reactive B cells was demonstrated via ex vivo and in vivo experiments with insulin-reactive B cell receptor transgenic mouse strains, VH125Tg/NOD and Tg125(H+L)/NOD. As an additional immune tolerance feature, the Y16A mutation of the insulin B (9-23) dominant T cell epitope was engineered into AKS-107 to suppress activation of insulin-specific T cells. In mice and non-human primates, AKS-107 was well-tolerated, non-immunogenic, did not cause hypoglycemia even at high doses, and showed an expectedly protracted pharmacokinetic profile. AKS-107 reproducibly prevented spontaneous diabetes from developing in NOD and VH125Tg/NOD mice that persisted for months after cessation of treatment, demonstrating durable immune tolerance. Discussion These preclinical outcomes position AKS-107 for clinical development in T1D prevention settings.