Editors' ChoiceSystemic Lupus Erythematosus

A Mimic for Lupus Treatment

Science Translational Medicine  06 Jul 2011:
Vol. 3, Issue 90, pp. 90ec106
DOI: 10.1126/scitranslmed.3002832

Abstract

Systemic lupus erythematosus (SLE) is a relatively common multisystem autoimmune disorder that is characterized by immune-mediated injury to a wide spectrum of organs, including the kidney, central nervous system, and joints. The prognosis can be quite variable, and patients may experience a relatively benign clinical course; however, in some situations patients develop substantial organ failure and rapidly progressive death. Although the exact cause of SLE is unknown, a large body of research has shown that organ damage occurs when pathogenic autoantibodies, particularly those targeting antinuclear proteins such as DNA, activate inflammation in target tissues. The titer of antibodies to DNA in a patient’s serum directly corresponds to disease activity, and antinuclear antibodies have also been shown to directly cause kidney damage, which is a major predictor of mortality. Treatment of severe disease includes generalized immunosuppression and medicines that target immune cell subsets such as B cells, the source of pathogenic autoantibodies. Now, a recent study by Bloom et al. presents important, stepwise progress toward the design of a novel blocking peptide that seeks to specifically neutralize pathogenic antibodies to DNA found in lupus patients.

In prior work, this group showed that antibodies to DNA from a lupus mouse model and in lupus patients bind not only DNA and kidney tissue, but also cross-react with the N-methyl-D-aspartate receptor (NMDAR) in neurons. They then use a mouse monoclonal antibody to DNA/NMDAR to establish that a specific target within NMDAR is the consensus peptide sequence DWEYS. Studies by this group and others have shown that the DWEYS peptide could be used as a blocking agent and a potential therapeutic, particularly when coupled with other compounds. This general approach was effective but limited by difficulties in manufacturing the compounds, some of which are immunogenic and have poor oral absorption. In the current study, the authors sought to address these issues by modifying a polyamine scaffold to generate a novel small molecule whose structure was predicted to mimic the properties of the DWEYS peptide. They name this peptidomimetic FISLE-412 and show in an enzyme-linked immunosorbent assay that it can inhibit both a mouse monoclonal antibody to DNA as well as autoantibodies from lupus patients from binding to the DWEYS peptide and to double-stranded DNA. They demonstrate that the inhibition is specific because FISLE-412 was ineffective at preventing binding to histone proteins. They then show that FISLE-412 can prevent autoantibodies of some lupus patients from binding to human renal tissue. In a final demonstration of the in vivo effectiveness of their peptide mimic, they use FISLE-412 in their mouse model of lupus neurotoxicity to prevent antibodies to DNA/NMDAR from causing excitotoxic death of neurons. This study provides exciting preclinical data for the use of peptidomimetics as highly specific, targeted treatments for systemic lupus erythematosus that may have the added advantage of avoiding the generalized immunosuppression often observed with standard therapies.

O. Bloom et al., Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity. Proc. Natl. Acad. Sci. U.S.A. 108, 10255–10259 (2011). [Abstract]