IMO-8400, a novel TLR7, TLR8 and TLR9 antagonist, inhibits disease development in mouse models of psoriasis (119.8)

Abstract

Abstract Toll-like receptors (TLR) are involved in the pathogenesis of numerous autoimmune diseases, including psoriasis. The role of TLR7 and TLR9 in psoriasis is well established and TLR8 may also contribute to this disease. Blocking the activation of these receptors through a TLR antagonist represents a novel approach to the treatment of psoriasis. We have developed IMO-8400, a synthetic DNA compound that inhibits TLR7-, TLR8-, and TLR9-mediated immune responses in cell-based assays. Additionally, following subcutaneous administration in non-human primates, it suppresses ex-vivo immune responses mediated through these receptors. IMO-8400 was evaluated in preclinical mouse models of psoriasis, induced by IL-23 cytokine or antimicrobial peptide LL-37. Psoriasis-like skin lesions were induced in the ear of C57BL/6 mice by intradermal injection of IL-23 or LL37. Injected mice were treated with subcutaneous administration of IMO-8400. Mice were euthanized at end of study and tissue samples were taken for histological examination. Increase in ear thickness was inhibited in a dose-dependent manner by treatment with IMO-8400. Reduction in epidermal hyperplasia and infiltrating leukocytes was observed in sample tissues. Treatment with IMO-8400 was associated with elevation of serum IL-10 levels. IMO-8400 can effectively suppress lesion development in these psoriasis models. IMO-8400 has potential as a novel agent for the treatment of psoriasis and other autoimmune diseases.