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

Front Immunol. 2024 Mar 7:15:1367514. doi: 10.3389/fimmu.2024.1367514. eCollection 2024.


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.

Keywords: Fc-fusion protein; antigen specific immunotherapeutic; autoimmunity; autoreactive B cell; insulin; insulin autoantigen; type 1 diabetes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B-Lymphocytes
  • Diabetes Mellitus, Type 1*
  • Humans
  • Immunotherapy
  • Islets of Langerhans*
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Receptors, Antigen, B-Cell


  • Receptors, Antigen, B-Cell

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported in part by a programmatic loan from The Leona M. and Harry B. Helmsley Charitable Trust and grants from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (#R43DK10799).