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

• Published in: Frontiers in immunology Vol. 15; p. 1367514
• Main Authors: Alleva, David G., Delpero, Andrea R., Sathiyaseelan, Thillainaygam, Murikipudi, Sylaja, Lancaster, Thomas M., Atkinson, Mark A., Wasserfall, Clive H., Yu, Liping, Ragupathy, Ramya, Bonami, Rachel H., Zion, Todd C.
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 07.03.2024
• Subjects: antigen specific immunotherapeutic; autoimmunity; autoreactive B cell; Fc-fusion protein; Immunology; insulin autoantigen; type 1 diabetes; type 1 diabetes; antigen specific immunotherapeutic; autoimmunity; autoreactive B cell; insulin; Fc-fusion protein; insulin autoantigen
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1367514

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. 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 and 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 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. These preclinical outcomes position AKS-107 for clinical development in T1D prevention settings.