Introduction to the use of belatacept: a fusion protein for the prevention of posttransplant kidney rejection

Biologics: Targets and Therapy, Oct 2012

Introduction to the use of belatacept: a fusion protein for the prevention of posttransplant kidney rejection Giovanbattista Ippoliti,1,2 Andrea Maria D'Armini,2 Marco Lucioni,3 Mazen Marjieh,1 Mario Viganò21UO Medicina Interna, Policlinico di Monza, Monza, Italy; 2Department of Surgical Sciences, Charles Dubost Transplant Center, Fondazione IRCCS San Matteo Hospital, 3Anatomic Pathology, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, ItalyAbstract: The development of new immunosuppressive drugs for kidney transplantation resulted both in better short-term outcomes and in decreased metabolic, cardiovascular, and nephrotoxicity risk. Belatacept belongs to a new class of immunosuppressive drugs that selectively inhibits T-cell activation by preventing CD28 activation and by binding its ligands B7-1 and B7-2. The result is an inactivation of costimulatory pathways. A comparative analysis of the BENEFIT and BENEFIT-EXT datasets showed belatacept regimens resulted in better cardiovascular and metabolic risk profiles than did cyclosporin A (CsA) regimens: belatacept likewise outperformed CsA in terms of lower blood pressure and serum lipids and less new onset diabetes after transplantation. About 20% of belatacept-treated patients developed adverse effects which included anemia, pyrexia, neutropenia, diarrhea, urinary tract infection, headache, and peripheral edema. At present, belatacept does not seem to predispose patients to a higher rate of infection than CsA maintenance immunosuppression. The risk of posttransplant lymphoproliferative diseases was higher in Epstein–Barr virus (EBV)-seronegative patients than in EBV-seropositive patients, but the risk may be reduced by use of a less intensive regimen and avoidance of EBV-negative patients and of patients whose pretransplant EBV serology is unknown. Belatacept provides a new option for immunosuppressive therapy in kidney transplantation, but needs further evaluation in terms of the late effects that may derive from prolonged blockage of the costimulatory system and the induction of tolerance status.Keywords: costimulation, organ transplantation, belatacept

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Introduction to the use of belatacept: a fusion protein for the prevention of posttransplant kidney rejection

Biologics:Targets and Therapy Introduction to the use of belatacept: a fusion protein for the prevention of posttransplant kidney rejection Giovanbattista Ippoliti 1 2 Andrea Maria D'Armini 1 Marco Lucioni 0 Mazen Marjieh 2 Mario Viganò 1 0 Anatomic Pathology, Foundation IRCCS Policlinico San Matteo, University of Pavia , Pavia , Italy 1 Department of Surgical Sciences, Charles Dubost Transplant Center, Fondazione IRCCS San Matteo Hospital 2 UO Medicina Interna, Policlinico di Monza , Monza , Italy The development of new immunosuppressive drugs for kidney transplantation resulted both in better short-term outcomes and in decreased metabolic, cardiovascular, and nephrotoxicity risk. Belatacept belongs to a new class of immunosuppressive drugs that selectively inhibits T-cell activation by preventing CD28 activation and by binding its ligands B7-1 and B7-2. The result is an inactivation of costimulatory pathways. A comparative analysis of the BENEFIT and BENEFIT-EXT datasets showed belatacept regimens resulted in better cardiovascular and metabolic risk profiles than did cyclosporin A (CsA) regimens: belatacept likewise outperformed CsA in terms of lower blood pressure and serum lipids and less new onset diabetes after transplantation. About 20% of belatacept-treated patients developed adverse effects which included anemia, pyrexia, neutropenia, diarrhea, urinary tract infection, headache, and peripheral edema. At present, belatacept does not seem to predispose patients to a higher rate of infection than CsA maintenance immunosuppression. The risk of posttransplant lymphoproliferative diseases was higher in Epstein-Barr virus (EBV)-seronegative patients than in EBV-seropositive patients, but the risk may be reduced by use of a less intensive regimen and avoidance of EBV-negative patients and of patients whose pretransplant EBV serology is unknown. Belatacept provides a new option for immunosuppressive therapy in kidney transplantation, but needs further evaluation in terms of the late effects that may derive from prolonged blockage of the costimulatory system and the induction of tolerance status. T-cells are important mediators of the immune response, and their activation is closely regulated to prevent autoreactivity. It is now recognized that the process of T-cell activation involves multiple signals and distinctly regulated pathways. costimulation; organ transplantation; belatacept - e d a o l n w o d y p a r e h T d n a s t e g r a T : s c i g o l o i B open access to scientific and medical research 8 1 0 2 l u J 2 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s e r .voepd l.yon the nuclear factor-kB. The activation of these transduction pathways leads to the linkage of IL-2 to its receptor (signal 3), whereupon the mammalian target of rapamycin is activated (Figure 1). These events collectively induce T-cell clonal proliferation and the generation of effector CD4+ T-cells (T-helpers) as well as a clonal expansion of activated CD8+ (cytotoxic T-cells). If the given pathway is blocked, T-cells do not receive a costimulation signal – they become anergic and undergo apoptosis.2,3 The costimulatory molecules may be divided into two categories: ( 1 ) positive costimulatory pathway (CD28/B7), which promotes T-cell activation; and ( 2 ) negative costimulatory pathway (CTLA4/B7), which antagonizes TCR signals and suppresses T-cell activation.4 The CD28 pathway The best characterized T-cell costimulatory pathway involves the CD28 receptor, which binds to costimulatory molecules named B7-1 (CD80) and B7-2 (CD86).5,6 CD80 //www lsue expression on resting cells is low, but it increases after pro:s an longed T-cell stimulation, and it thus plays a role in perpetuttph rsoe ating immune response. CD86 is expressed constitutively, frodm ropF is rapidly upregulated on APCs upon signal 1, and may be de important in the mediation of initial T-cell activation.7 a o l n w o d y rap Antigen presenting cell e h T d n tsea Signal 1 Signal 2 g r a ili:scogT MHACntIiIgen B-7 o B CD45 CD4 CD3 CD28 TCR Ca2+ Calcineurin Nucleus NFAT Cytokine induction T lymphocyte The CD28 molecule, which is constitutively expressed on all naïve CD4 and CD8 T-cells, is the most important activating costimulation receptor of T-cells, in concert with TCR. After interaction with its ligands, CD28 promotes T-cell differentiation into TH1 cells, enhances both the production of antibodies by B-cells and the proliferation of previously activated T-cells and causes the production of cytokine, including IL-2 and IFN-y.6 Moreover, the CD28/B-7 signals induce the development of a class of T-cells termed as regulatory T-cells (Tregs), which inhibit immune response and mantain self-tolerance.8 The CTLA-4 pathway After the identification of the CD28 molecule and its role in T-cell activation, it was found that CTLA-4 (CD152) and CD28 bind the same ligands (B7-1 and B7-2), but CTLA-4 binds with far higher affinity: 2500-fold avidity for B7-1 (...truncated)


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Giovanbattista Ippoliti, Andrea Maria D'Armini, Marco Lucioni, Mazen Marjieh, Mario Viganò. Introduction to the use of belatacept: a fusion protein for the prevention of posttransplant kidney rejection, Biologics: Targets and Therapy, 2012, pp. 355-362, DOI: 10.2147/BTT.S27565