A Novel Approach in Kidney Transplantation: Costimulation Blockade

1. A Novel Approach in Kidney Transplantation: Costimulation Blockade Reference: Snanoudj R, Zuber J, Legendre C. Costimulation blockade as a new strategy in kidney transplantation. Drugs. 2010;70(16):2121–2131.

2. Over the past 5 decades, immunosuppressive regimens for kidney transplantation have significantly improved; however, these agents have had little impact on long-term graft survival. • The reason being in part, to the broad nonimmune effects of the current immunosuppressive drugs, which are involved in the death of patients and in chronic allograft dysfunction mostly due to their nephrotoxicity. • However, recent progress in the development of biologicals like antibodies and fusion proteins, allows the precise targeting of the immune system, preventing the nonimmune side-effects encountered with current protocols.

3. Apart from immunological factors, current immunosuppressive protocols are involved in several mechanisms in the development of chronic graft dysfunction (see Table 1). • As a result, recent immunosuppressive protocols tend to minimize or even avoid the use of calcineurin inhibitors (CNIs). Presently, it is obvious that complete withdrawal of CNIs from the gold standard triple therapy (with corticosteroids and mycophenolate mofetil) results in a significant increase in the rate of late acute rejection. • Therefore, the complete avoidance of CNIs is a challenge, as preventing their toxic effects should not be associated with an increased risk of triggering an alloimmune response. • An attractive alternative is the use of costimulation blockade that allow the precise and efficient immune targeting with a favorable safety profile.

5. Costimulation Blockade: Immunological Basis Three Signals Engaged in T-Cell Activation • T-lymphocyte activation requires three signals, which are shown in Figure 1. The first involves T-cell receptor triggering by donor antigen on the surface of dendritic cells (DCs) or other antigen-presenting cells. • The second, or costimulation signal, which is not nantigen-dependent is delivered when B7-1/CD80 and B7-2/CD86 on the surface of DCs engage CD28 on T cells. • These two signals are necessary to activate three transduction pathways that result in interleukin-2 binding to its receptor, which is the third signal, and the downstream mammalian target of rapamycin pathway activation, leading to T-cell clonal proliferation and the generation of effector T cells.

6. The Intricacy of the B7/CD28/CTLA4 Conduit • The B7/CD28/CTLA4 pathway is characterized by the dual affinity of B7-1 and B7-2 for both the stimulatory receptor CD28 and the inhibitory receptor (cytotoxicTlymphocyte- associated antigen 4 (CTLA4) or CD152). • The CD28 molecule, which is constitutively expressed on T cells, provides a T-cell activation signal. • Contrarily, the expression CTLA4 is rapidly upregulated following T-cell activation, and delivers a T-cell inhibition signal due to its higher receptor affinity for both B7-1 and B7-2. • CTLA4 plays a critical role in downregulating the T-cell response, primarily by interrupting T cell–DC interactions.

8. From Experimental Models of ‘Classical’ Costimulation Blockade with CTLA4-Ig to Clinical Studies with Belatacept • One of the foremost tools used to target the B7/CD28 pathway was the CTLA4 immunoglobulin (Ig) (abatacept) molecule. • However, insufficient blockade of the CD28/ B7 interaction could partly account for the limited results obtained in non-human primate (NHP) models. • Recently, two amino acid substitutions in the CTLA4 binding domain were identified as potentially useful, leading to the development of a new molecule, belatacept (LEA29Y). • With this, inhibition of T-cell activation was increased 10- fold over that of CTLA4-Ig. Moreover, NHP studies showed a prolongation of kidney allograft survival and an inhibition of antidonor humoral response when belatacept was used alone or in combination with corticosteroids and MMF.

9. A large-scale 12-month phase II multicenter study was conducted with belatacept in renal transplantation. • Here, the primary noninferiority objective was reached, with very low and similar incidences of acute rejection at 6 months. • The glomerular filtration rate at 12 months was significantly higher in patients receiving belatacept than in those treated with ciclosporin. • In addition, the incidence of chronic allograft nephropathy (scarring lesions) was lower in patients receiving belatacept by month 12. • As for the adverse effects, the frequency of infections was found to be similar. • Many other preliminary results have also suggested that the use of belatacept in CNI and corticosteroid avoiding regimens, in combination with rabbit antithymocyte globulin (ATG) induction, might be a promising avenue for future trials. • Importantly, no case of post-transplantation lymphoproliferative disorder (PTLD) was observed at 6 months in these patients.

10. Aiming Other Costimulatory Pathways The CD40/CD40L Pathway • The second major costimulatory pathway of interest in transplantation immunology is the CD40/CD40L pathway. • The CD40 is constitutively expressed on B cells, DCs, and macrophages. • Several studies have suggested that the inhibition of CD40-mediated signaling events is an important mechanism of action for both anti-CD40 and anti-CD40L antibodies. Other Members of the CD28/B7 and Tumor Necrosis Factor (TNF)/TNF Receptor Super-families • Several other members of the CD28/B7 and TNF/TNF receptor super-families deliver positive or negative costimulatory signals, either early or delayed after encountering an antigen.

11. Aiming Other Costimulatory Pathways The Leukocyte Function-Associated Antigen (LFA)- 1/Intercellular Adhesion Molecule (ICAM) Pathway: • Leukocyte function-associated antigen-1 is a β2-integrin expressed on T cells, chiefly memory T cells. • The introduction of efalizumab, a humanized anti-CD11a mAb that blocks the binding of LFA-1 to ICAM-1 has received US FDA approval for treatment of severe plaque psoriasis. • However, owing to the occurrence of progressive multifocal leukoencephalopathy, a potentially fatal JC polyomavirusassociated disease in four patients treated for psoriasis, it has been decided to initiate the progressive withdrawal of efalizumab.

12. Aiming Other Costimulatory Pathways • The CD2/LFA-3 Pathway: Alefacept (LFA-3-Ig) is a fusion protein consisting of the CD2-binding portion of human LFA-3 linked to the Fc portion of human IgG1. • The FDA approved alefacept for use in severe plaque psoriasis. • Alefacept has been shown to increase allograft cardiac survival and, more interestingly, to prevent kidney allograft rejection and alloantibody formation in combination with CTLA4-Ig. • Presently, two phase II multicenter studies are being conducted to assess the efficacy and safety of alefacept in renal transplant recipients.

13. Conclusion • Belatacept is reportedly believed to become a first-line immunosuppressive molecule given its short-term favorable efficacy/safety ratio. • This drug along with other costimulatory blocking agents in development are foreseen as components of a combination therapy applied with other biologicals or with lower doses of classical immunosuppressive drugs. • Apart from the clear benefits in terms of cardiovascular risks and nephrotoxicity afforded by these biologicals, concerns about infectious and neoplastic complications call for a closely explored study in future research. • Nevertheless, this family of immunosuppressants could be a powerful tool in the road to transplantation tolerance. • Additional studies are required to find the adequate combinations of molecules and the monitoring tools to identify the appropriate moment and candidates for reduction and even weaning of immunosuppression.