Advances in SLE Treatment: The IRAK1/4 Inhibitor R835 as a Promising Therapeutic Agent

Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder that manifests through the breakdown of immune tolerance, leading to immune cell hyperactivity, proinflammatory cytokine generation, and end-organ damage due to immune complex accumulation. Toll-like receptors (TLRs), crucial for innate immune reactions to pathogens and danger signals, are implicated in SLE's development by recognizing self-proteins. Interleukin receptor-associated kinases (IRAK) 1 and 4 initiate MyD88-dependent signaling pathways from TLRs and Interleukin-1 Receptors (IL-1R), making them promising targets for SLE therapy. A phase 1 study has shown that R835, a potent and selective IRAK1/4 inhibitor, significantly reduced LPS-induced serum cytokines in healthy volunteers.

The objective of the study was to explore the therapeutic potential of IRAK1/4 inhibition in SLE by assessing the impact of R835 on TLR7 signaling and its efficacy in a mouse model exhibiting lupus-like symptoms.

The methodology involved stimulating human primary dendritic cells and whole blood with gardiquimod, a TLR7 agonist, to measure R835's effect on Interferon-alpha (IFN-α) production. The compound was also tested for its effectiveness on survival and disease progression in lupus-prone NZB/W F1 mice, either at an early stage or with active disease.

The results showed that R835 effectively suppressed TLR7-induced cytokine production in human cells and reduced serum IFN-α levels in mice in a dose-dependent manner following TLR7 agonist administration. In lupus-prone mice, R835 treatment reversed the progression of the disease and the establishment of a pro-inflammatory environment, evidenced by decreased proteinuria, blood urea nitrogen, autoantibodies, and improved renal pathology.

R835 is the first dual IRAK1/4 inhibitor to enter clinical trials and presents a promising therapeutic approach for autoimmune and rheumatic diseases, including SLE. The study's authors are affiliated with Rigel Pharmaceuticals, indicating a potential conflict of interest.