**7. Anticomplement antibody**

Patients with SLE have widespread activation and deposition of the complement fragment in affected tissues. In murine models of SLE, the administration of the anti-C5 monoclonal antibody delayed the onset of proteinuria and prolonged survival. Moreover, pharmacological blockade of C5 receptor with a specific receptor antagonist reduces disease manifestation in experimental lupus nephritis (Cordeiro & Isenberg 2008). Furthermore, in mice with renal disease induced by a human anti-dsDNA antibody, RH-14 anti-C5 monoclonal antibody significantly reduced proteinuria.

Eculizumab (Soliris; Alexion Pharmaceuticals, Inc., Cheshire, CT) is a recombinant humanized monoclonal antibody that works by binding to complement protein C5, inhibiting its enzymatic cleavage, blocking formation of the terminal complement complex, and thus preventing red cell lysis (Parker , Kar et al. 2007). It has a molecular weight of 148 kD. Eculizumab is approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) (Hillmen, Young et al. 2006). This antibody is potentially useful for treating patients with lupus nephritis. In this disease, the terminal components of the complement C5b-C9 play an important role in mediating the inflammation and the damage of podocytes and glomerular basement membrane (Robak & Robak 2009). Eculizumab has been recently developed and investigated in a phase I single dose study in SLE.

pharmacokinetics (Davis, Totoritis et al. 2001). All patients experienced at least one adverse event. However, no infusion related cytokine-release syndrome was observed and all patients completed treatment. In a phase II, double blind, placebo-controlled, multiplecenter, multiple-dose study, 85 patients with mild-to-moderately active SLE were randomized to receive 6 infusions of IDEC-131, ranging from 2.5 mg/kg to 10.0 mg/kg, or placebo over 16 weeks (Kalunian, Davis et al. 2002). At week 20, the mean change from baseline total SLEDAI scores indicated improvement in disease activity within each treatment group. In addition, the median global BILAG scores at week 20 indicated a reduction in SLE activity. However, results did not differ among the IDEC-131 treatment and placebo groups, and no dose-response relationship was noted at week 20. Moreover, the changes in levels of anti-dsDNA antibody and serum complement were not statistically significant in any group or between treatment groups and placebo. In addition, the changes in levels of anti-dsDNA antibody and serum complement were not different between treatment groups and placebo. The adverse events were also similar between the IDEC-131

BG9588 (Biogen, Inc., Cambridge, MA) is a recombinant humanized anti-human CD40L monoclonal antibody that specifically binds to the CD40 ligand expressed on the surface of activated T lymphocytes. It blocks the CD40L/CD40 interaction between T and B cells that is required for the initiation for certain antibody responses. A short course of BG9588 treatment in patients with proliferative lupus nephritis reduced anti-dsDNA antibodies, increased C3 concentrations, and decreased hematuria (Boumpas, Furie et al. 2003). These results indicate that the drug has immunomodulatory action. Additional studies will be

Patients with SLE have widespread activation and deposition of the complement fragment in affected tissues. In murine models of SLE, the administration of the anti-C5 monoclonal antibody delayed the onset of proteinuria and prolonged survival. Moreover, pharmacological blockade of C5 receptor with a specific receptor antagonist reduces disease manifestation in experimental lupus nephritis (Cordeiro & Isenberg 2008). Furthermore, in mice with renal disease induced by a human anti-dsDNA antibody, RH-14 anti-C5

Eculizumab (Soliris; Alexion Pharmaceuticals, Inc., Cheshire, CT) is a recombinant humanized monoclonal antibody that works by binding to complement protein C5, inhibiting its enzymatic cleavage, blocking formation of the terminal complement complex, and thus preventing red cell lysis (Parker , Kar et al. 2007). It has a molecular weight of 148 kD. Eculizumab is approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) (Hillmen, Young et al. 2006). This antibody is potentially useful for treating patients with lupus nephritis. In this disease, the terminal components of the complement C5b-C9 play an important role in mediating the inflammation and the damage of podocytes and glomerular basement membrane (Robak & Robak 2009). Eculizumab has been recently

and placebo groups.

needed to evaluate its long-term effects.

monoclonal antibody significantly reduced proteinuria.

developed and investigated in a phase I single dose study in SLE.

**7. Anticomplement antibody** 

**6.2.2 BG9588** 


The Emerging Role of Monoclonal Antibodies in the Treatment of Systemic Lupus Erythematosus 269

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**10. References** 

2626

1806-1816, ISSN 0149-2918

1016, ISSN 0003-4967


ADCC=antibody-dependent cellular cytotoxicity; BLyS=B-lymphocyte Stimulator; CDC=complement-dependent cytotoxicity; mAb= monoclonal antibody; SMIP=small modular immunopharmaceutical

Table 1. Monoclonal antibodies potentially useful in systemic lupus erythematosus
