Soluble Antigen Arrays Efficiently Deliver Peptides and Arrest Spontaneous Autoimmune Diabetes

Abstract

Antigen-specific immunotherapy (ASIT) offers a targeted treatment of autoimmune diseases that selectively inhibits autoreactive lymphocytes, but there remains an unmet need for approaches that address their limited clinical efficacy. Soluble Antigen Arrays (SAgAs) deliver antigenic peptides or proteins in multivalent form, attached to a hyaluronic acid backbone using hydrolysable linkers (hSAgA) or stable “click” chemistry linkers (cSAgA). They were evaluated for the ability to block the spontaneous development of disease in the non-obese diabetic mouse model of Type 1 diabetes (T1D). Two peptides, a hybrid insulin peptide and a mimotope, efficiently prevented the onset of T1D when delivered in combination as SAgAs, but not individually. Relative to free peptides administered at equimolar dose, SAgAs (particularly cSAgA) enabled a more effective engagement of antigen-specific T cells with greater persistence and induction of tolerance markers such as CD73, IL-10, PD-1, KLRG-1. Anaphylaxis caused by the free peptides was attenuated using hSAgA and obviated using cSAgA platforms. Despite similarities, the two peptides elicited largely non-overlapping and possibly complementary responses among endogenous T cells in treated mice. Thus, SAgAs offer a novel and promising ASIT platform superior to soluble peptides in inducing tolerance while mitigating risks of anaphylaxis for the treatment of T1D.