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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Anti-Ccl2 Spiegelmer Permits 75% Dose Reduction of Cyclophosphamide to Control Diffuse Proliferative Lupus Nephritis and Pneumonitis in MRL-Fas(lpr) Mice

Nephrological Center, Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany (O.K., R.A., R.D.P., S.P., S.S., H.-J.A.); and NOXXON Pharma AG, Berlin, Germany (D.E., N.S., S.Z., S.K.)

Cyclophosphamide (CYC) can control diffuse proliferative lupus nephritis (DPLN) by potent immunosuppression but remains associated with serious and life-threatening complications. Drugs that specifically target mediators of DPLN may help to reduce CYC dose and side effects. Monocyte chemoattractant protein (MCP-1)/CCL2 mediates monocyte and T cell recruitment in DPLN and Ccl2-specific L-enantiomeric RNA Spiegelmer mNOX-E36 neutralizes the biological effects of murine Ccl2 in vitro and in vivo. We injected MRL^lpr/lpr mice with DPLN from 14 weeks of age with vehicle, weekly 30 mg/kg CYC (full dose), monthly 30 mg/kg CYC (one-fourth full dose), pegylated control Spiegelmer, pegylated anti-Ccl2 Spiegelmer (3/week), pegylated anti-Ccl2 Spiegelmer plus CYC one-fourth full dose and mycophenolate mofetil. At week 24, DPLN and autoimmune lung injury were virtually abolished with CYC full dose but not with CYC one-fourth full dose. The CYC one-fourth full dose/Spiegelmer combination was equipotent to CYC full dose on kidney and lung injury. CD3⁺CD4^-CD8^- and CD3⁺CD4⁺CD25⁺ T cells and serum interleukin-12p40 and tumor necrosis factor- levels were all markedly affected by CYC full dose but not by CYC one-fourth full dose. No additive effects of anti-Ccl2 Spiegelmer were noted on bone marrow colony-forming unit-granulocyte macrophage counts and 7/4^high monocyte counts, lymphoproliferation, and spleen T cell depletion. In summary, anti-Ccl2 Spiegelmer permits 75% dose reduction of CYC for controlling DPLN and pneumonitis in MRL-Fas(lpr) mice, sparing suppressive effects of full-dose CYC on myelosuppression and T cell depletion. We propose anti-Ccl2 Spiegelmer therapy as a novel strategy to reduce CYC toxicity in the treatment of severe lupus.

Address correspondence to: Hans-Joachim Anders, Medizinische Poliklinik der LMU, Pettenkoferstr. 8a, 80336 Munich, Germany. E-mail: hjanders{at}med.uni-muenchen.de