ERLANGEN, Germany—The proteasome inhibitor bortezomib (Velcade^®, Millenium Pharmaceuticals) prevented nephritis and prolonged survival in two mouse models of systemic lupus erythematosus, and the drug is a strong candidate for clinical trials in human patients, German researchers report in Nature Medicine.¹

“[T]he elimination of autoreactive plasma cells by proteasome inhibitors might represent a new treatment strategy for antibody-mediated diseases,” said lead investigator Kirsten Neubert, MD, of the Nikolaus Fiebiger-Center of Molecular Medicine at University Hospital in Erlangen, Germany.

Bortezomib, which is approved in the US for treatment of multiple myeloma, eliminated both short- and long-lived plasma cells in two mouse models of lupus (NZB/W F1 mice and MRL/lpr lupus mice), both of which spontaneously develop a lupus-like syndrome.

“Treatment with bortezomib depleted plasma cells producing antibodies to double-stranded DNA, eliminated autoantibody production, ameliorated glomerulonephritis, and prolonged survival [of the mice],” Dr. Neubert reported.

In the NZB/W F1 mice, all 20 bortezomib-treated mice, but only 1 of 10 untreated control mice, survived to 56 weeks. “Of note, all bortezomib-treated mice remained healthy without overt signs of disease or toxicity,” the authors write.

None of the bortezomib mice developed proteinuria, although 9 of 10 control mice had proteinuria by 32 weeks. Histopathology studies showed little if any signs of glomerular damage in the treated mice.

Bortezomib also reduced kidney damage in mice that had already developed antibodies to double-stranded DNA (dsDNA).

One of 10 bortezomib-treated mice compared with 4 of 8 placebo-treated mice died before the end of the experiment.

“[B]ortezomib not only prevented but also reverted high dsDNA-specific antibody titers and proteinuria in NZB/W F1 mice with established kidney disease,” Dr. Neubert said.

Studies in the MRL/lrp lupus mice suggest that intermittent treatment with bortezomib might be enough to induce and maintain these benefits. These mice were treated for 4 weeks, then again after anti-dsDNA levels began to rise. This schedule resulted in a decrease in proteinuria, complete prevention of lupus-like skin lesions, and significantly longer survival.

“These data indicate that interval treatment is sufficient to control lupus-like disease,” Dr. Neubert said. The researchers describe this as the first therapeutic approach that can deplete plasma cells “without causing overt toxic effects in mice.”

Reference

1. Neubert K, Meister S, Moser K, et al. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nature Medicine 2008;[Epub ahead of print] 8 June 2008; doi:10.1038/nm1763