Novel B Cell Therapeutic Targets in Transplantation and Immune-Mediated Glomerular Diseases

Abstract

B cells and antibodies play an important role in the alloresponse to renal grafts as well as in immune-mediated glomerular diseases. In transplantation, greater recognition and improved diagnosis of antibody-mediated rejection have been a catalyst to the introduction of newer drugs and regimens that target B cells, plasma cells, and donor-specific antibodies to improve the outcome associated with antibody-mediated rejection. In immune-mediated renal disease, novel and more selective B cell therapies are gradually modifying the traditional therapeutic approach that consists of steroids and other immunosuppressants. A new era of selective and more effective immunosuppression agents that target the humoral response is finally emerging in transplantation and renal diseases.Clin J Am Soc Nephrol 5: 142-151, 2010. doi: 10.2215/CJN.04580709 B cells and antibodies play a critical role both in the alloresponse after renal transplantation and in immune-mediated glomerular diseases. In transplantation, B cells, in addition to their role in the humoral response to alloantigens, act as efficient antigen-presenting cells and thus participate in the activation of T cells (1). The development of more sensitive solid phase-based serologic assays for detecting anti-HLA antibodies and the routine use of C4d (a complement fragment considered a marker of antibody deposition) staining in kidney biopsies have led to better recognition of the importance of both acute and chronic antibody-mediated rejection on graft outcome (2,3). The role of B cells in generating and perpetuating alloantibody production has provided the rationale for the use of anti-B cell therapies in desensitization of highly sensitized patients, decreasing the titer of donor-specific antibodies (DSA) and reversing acute antibody-mediated rejection after transplantation (4).In glomerular diseases that are suspected to be mediated by B cells and antibodies, novel and more selective targeting of B cells is gradually altering the traditional therapeutic approach that consists of steroids and other immunosuppressive drugs (Table 1). In this review, we summarize clinical trials in renal transplantation and immune-mediated glomerular diseases using novel therapies that target B cells and antibodies. Novel Anti-B Cell TherapiesThe anti-B cell agent most frequently used, albeit off-label, in renal transplantation and in glomerular diseases is rituximab. Rituximab, a chimeric monoclonal antibody (mAb) that is approved for use in B cell lymphoma and rheumatoid arthritis, binds to the CD20 receptor of B cells and depletes them through complement-dependent cytotoxicity, antibody-dependent cytotoxicity, and stimulation of B cell apoptosis (4,5). B cell depletion with rituximab may persist for Ն6 mo and is followed by a repopulation of B cells that are deficient of the CD27 receptor, a marker for memory B cells. Repopulation of naive B cells and the persistence of normal Ig levels impart to rituximab both its efficacy and safety (5). For decreasing the potential immunogenicity tha...

Desensitization Protocols and Their Outcome

“…There are also new anti-B cell agents in the pipeline that were recently reviewed in detail (102). These include ocrelizumab and ofatumumab (humanized anti-CD20 mAb with decreased immunogenicity), epratuzumab (humanized anti-CD22 mAb), belimumab (humanized mAb to Blys, also known as BAFF [i.e., B cell activation factor]), and atacicept (fusion receptor protein that inhibits Blys and April).…”

Updates on the Treatment of Lupus Nephritis

“…Rituximab, a chimeric half murine-half human anti-CD20 monoclonal antibody, has been associated with the development, in approximately 10% of treated patients, of human anti-chimeric antibodies that are of uncertain significance. 51,52 These antibodies have the potential to block the efficacy of future doses of rituximab. The design of Study to Evaluate Ocrelizumab in Patients With Nephritis Due to Systemic Lupus Erythematosus was based, in part, on the hope that ocrelizumab would have better outcome and safety profiles than rituximab because of the absence of human anti-chimeric antibody formation; however, the trial wasstoppedprematurelybecauseofmoreserious and opportunistic infections than expected in recipients of ocrelizumab than placebo.…”

New and emerging treatments for lupus nephritis

“…This carries the theoretical advantages of avoiding fi rst dose transfusion reactions and the development of human anti-chimeric antibodies (HACA) seen in approximately 10% of patients treated with rituximab. 40,41 While the clinical signifi cance of HACA is unclear, they may block the effi cacy of repeated doses of rituximab. However, the Study to Evaluate Ocrelizumab in Patients with Nephritis Due to Systemic Lupus Erythematosus (BELONG) was suspended prematurely due to an increased incidence of serious and opportunistic infections in the treatment group.…”