Recombinant human Dnase I (rhDNase) in patients with lupus nephritis

Systemic lupus erythematosus (SLE) is characterized by the production of pa thogenic autoantibodies to nucleoprotein antigens, including double-strande d DNA (dsDNA). The deposition of IgG dsDNA immune complexes in glomeruli is thought to be crucial for disease pathogenesis and complement activation. rhDNase catalyzes the hydrolysis of extracellular DNA and has been shown to delay the development of dsDNA antibodies, reduce proteinuria, and delay m ortality in a lupus-prone murine model. We conducted a 40d, phase Ib, randomized, double-masked, placebo-controlled trial to determine the safety and pharmacokinetics of rhDNase, and to meas ure any changes in markers of disease activity in 17 patients with lupus ne phritis. Patients were assigned to receive either: (1) 25 mu g/kg,rhDNase ( n = 8); (2) 125 mu g/kg rhDNase (n = 6); or (3) placebo (n = 3) initial sin gle intravenous (IV) dose followed by 10 subcutaneous (SC) doses. Skin biop sies performed on nine patients pre- and post-treatment were studied for im mune complex deposition by immunofluorescence.Serum cytokine levels (sIL2-R , IL-6, IL-10, and TNF-alpha) were analyzed by ELISA. Cytokine secretion an d antibody production were measured by ELISPOT analysis and ELISA. Serum hydrolytic activity of rhDNase was achieved after IV administration a t 25 and 125 mu g/kg, but not after SC administration at either dose. A t1/ 2 of 3-4h was estimated from serum concentration profiles following IV admi nistration. Serum dsDNA antibodies were unchanged (mean values: 33IU/mL vs 39IU/mL [pre- and post-treatment] for the 25 mu g/kg group, and 74IU/mL vs 74IU/mL for the 125 mu g/kg group, and 14IU/mL vs 20IU/mL for the placebo g roup). Complement levels (C3 and C4) and circulating immune complexes did n ot change appreciably during the treatment period for any of the groups. Se rum cytokine profiles by ELISA revealed no changes in sIL-2 receptor, IL-6, IL-10, or TNF-alpha. There was no change in the number of cells secreting either Th1 or Th2 specific cytokines, nor in the number of cells secreting dsDNA antibodies. Neutralizing antibodies to rhDNase were not detected in s erum at any time during the study. Immune complex deposition was unchanged in pre- and post-treatment in skin biopsies in both dose groups. rhDnase was well tolerated without significant adverse events following adm inistration, and treatment was not associated with the development of neutr alizing antibodies to rhDNase. Serum rhDNase concentrations capable of hydr olytic activity of rhDNase were achieved for a few hours following IV, but not SC administration. Serum markers of disease activity were unchanged dur ing the study period.