A CD40-targeting peptide, OPT501, modulates inflammation in canine diabetes mellitus improving clinical outcomes.

Abstract

INTRODUCTION: The etiology of Canine Diabetes Mellitus (CDM) is poorly understood but findings like increased CD3CD4CD40pathogenic effector T cells (Th40 cells), support an autoimmune contribution. Despite insulin supplementation and possible residual C-peptide in CDM, many dogs remain severely dysglycemic, with weight loss, cataracts, and chronic and recurrent infections. In human and murine autoimmune disease, CD40-CD154 acts as a prominent inflammation driver but targeting that interaction, and others, with antibodies has been plagued by complications such as thrombotic emboli or immunosuppression. We developed small peptides that target CD40 and that are not accompanied by the side effects attributed to antibodies. In mice, such a peptide prevented and reversed type 1 diabetes. METHODS: We utilized a CD40-targeting peptide, OPT501, to treat CDM dogs via an intravenous or subcutaneous route and followed their disease status and clinical outcomes as well as their inflammatory status. RESULTS: Treatment with OPT501 significantly decreased pathogenic Th40 cells, the systemic inflammatory index, and fructosamine (an analog to human HbA1c). This led to lowered insulin requirements while improving blood glucose regulation. OPT501 also significantly reduced cholesterol and alkaline phosphatase, and significantly increased plasma C-peptide, a measure of endogenous insulin production. CONCLUSIONS: This pilot and proof-of-concept study demonstrates that targeting CD40 with a peptide is feasible and impacts the inflammatory status of the recipient CDM dogs, with improved disease management as a result. The C-peptide result is consistent with preservation of islet beta cell health and function. These data support translation of a CD40 targeting peptide approach to human type 1 diabetes.