Therapeutic Interruption of Protein Degradation

Some antibodies that bind ‘self’ molecules (autoantibodies) can signal and even cause autoimmune diseases. Antibodies are produced by B cells, largely by a differentiated, typically short-lived variety called plasma cells (PC), which dedicate 10-20% of their protein-synthesis capacity to immunoglobulin. PC develop in the germinal centers of lymph nodes and spleen and then migrate to the bone marrow, where a subset endures. Treatments that target B cells, such as Rituxan, might often fail to substantially reduce autoantibodies because PC are resistant.

Neubert and colleagues reasoned that precisely the hallmark of PC – their high rate of protein synthesis – could sensitize them to bortezomib (Bz, Velcade), a proteasome inhibitor that is therapeutic in some cancers. Bz interferes with the ubiquitin protein degradation pathway, thereby blocking NF-kB release and promoting the unfolded protein ‘stress’ response that induces apoptosis. Here, they show that Bz reduced short- and long-lived PC (CD138+ CD25- cells with cytoplasmic immunoglobulin light or heavy chains) ~90% in the bone marrow and spleens of mice after just 48 h treatment. Antibody-secreting cells remained decreased during 8 weeks of treatment. Bz had little or no effect on total B cell numbers or many B cell subsets, although germinal center B cells were reduced (Fig. 1). Cyclophosphamide or dexamethasone were less effective in reducing the numbers of long-lived (BrdU-) PC, suggesting a cellular basis for the failure of these current therapeutics in reducing autoantibodies (Fig. 2). In bone marrow and splenic PC, Bz rapidly induces transient expression of CHOP (20-40 fold within 4 h), a signaling protein previously implicated in the apoptotic response to the stress of protease inhibitors.

Lastly, they treated lupus-prone mice (NZB/W F1) with Bz and found it prevented onset of kidney disease (measured by proteinuria) and death. Remarkably, Bz was therapeutic in early disease, reducing serum levels of the autoantibody associated with kidney disease and preventing proteinuria in this lupus model as well as another (MRL/lpr: shown, dotted line Bz treated, solid line control treated, from Fig. 5a).

As Bz is already approved for use in humans, it should not be long before we know its therapeutic efficacy in lupus and other autoimmune diseases. Also, a new generation of proteasome inihibitors that target specific steps in the process are ready to be tested.

Neubert K, Meister S, Moser K, Weisel F, Maseda D, Amann K, Wiethe C, Winkler TH, Kalden JR, Manz RA, Voll RE. “The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis” Nat Med. 2008 Jun 8.