ABSTRACT
Accumulating evidence supports the potential of proteasome inhibitors as immunosuppressants. Proteasome inhibitors interfere with antigen processing and presentation, as well as with the signaling cascades involved in immune cell function and survival. Both myeloma and healthy plasma cells appear to be highly susceptible to proteasome inhibitors due to impaired proteasomal activity in both cell types. As a consequence, these agents can be used to reduce antibody production and thus prevent antibody-induced tissue damage. Several clinical studies have explored the potential of bortezomib, a peptide boronate proteasome inhibitor, for treating immune disorders, such as antibody-mediated organ rejection and graft-versus-host disease (GVHD), with encouraging results. Here, we discuss the biological rationale for the use of proteasome inhibitors as immunosuppressive agents and review the clinical experience with bortezomib in immune-mediated diseases.
Subject(s)
Graft Rejection/drug therapy , Graft vs Host Disease/drug therapy , Immunosuppressive Agents/immunology , Immunosuppressive Agents/therapeutic use , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors/immunology , Proteasome Inhibitors/therapeutic use , Animals , Antibodies/immunology , Boronic Acids/immunology , Boronic Acids/therapeutic use , Bortezomib , Graft Rejection/enzymology , Graft Rejection/immunology , Graft vs Host Disease/enzymology , Graft vs Host Disease/immunology , Humans , Pyrazines/immunology , Pyrazines/therapeutic useABSTRACT
Monoclonal antibodies have been the most successful therapeutics ever brought to cancer treatment by immune technologies. The use of monoclonal antibodies in B-cell Non-Hodgkin's lymphomas (NHL) represents the greatest example of these advances, as the introduction of the anti-CD20 antibody rituximab has had a dramatic impact on how we treat this group of diseases today. Despite this success, several questions about how to optimize the use of monoclonal antibodies in NHL remain open. The best administration schedules, as well as the optimal duration of rituximab treatment, have yet to be determined. A deeper knowledge of the mechanisms underlying resistance to rituximab is also necessary in order to improve the activity of this and of similar therapeutics. Finally, new antibodies and biological agents are entering the scene and their advantages over rituximab will have to be assessed. We will discuss these issues and present an overview of the most significant clinical studies with monoclonal antibodies for NHL treatment carried out to date.
