Preclinical To Clinical Translation Of Cenerimod, A Novel S1p(1) Receptor Modulator, In Systemic Lupus Erythematosus

Both B and T lymphocytes have been implicated in playing a major role in the pathogenesis of systemic lupus erythematosus (SLE), a complex and heterogeneous autoimmune disease of unknown aetiology, characterised by the production of high titres of pathogenic autoantibodies, infiltrating lymphocytes and tissue damage across multiple organ systems.1\n\nIn SLE, T lymphocytes orchestrate pathogenesis by directly driving organ damage and additionally by supporting B lymphocyte activation and proliferation, thus enabling the maturation of autoantibody-producing B lymphocytes, so-called antibody-secreting cells (ASC). ASC represent proliferative plasmablasts and plasma cells which are the predominant effector B lymphocytes in pathogenic conditions of autoimmunity.2 3 Increased numbers of ASC correlate with various aspects of disease activity in patients with active SLE.4–6\n\nConcomitant to the changes in immune lymphocyte populations observed in patients with SLE, the inflammatory environment in SLE is reminiscent of a chronic interferon (IFN)-driven immune response associated with viral infections. These include sustained expression of type I IFNs, often referred to as the ‘IFN signature’,7–9 and an increase in IFN-responsive chemokines such as CXCL9 and CXCL10. Additionally, increases in modulators associated with SLE pathology such as interleukin 6 (IL-6) and tumor necrosis factor (TNF) exacerbate the inflammatory environment in SLE.10\n\nOne key aspect of the inextricable network between immune lymphocytes and the inflammatory environment is the interaction between lymphocytes and chemokine gradients, underlying the tightly controlled process of immune lymphocyte migration, which is fundamental in driving an adaptive immune response. The sphingosine-1-phosphate (S1P) chemotactic gradient is the predominant factor for lymphocyte egress out of peripheral lymphoid organs into the lymphatic and vascular circulation via S1P/S1P1 receptor engagement on B and T lymphocytes.11 S1P1 receptor modulators are approved to treat multiple sclerosis and have shown clinical benefit in other diseases, providing evidence that this mode …