Use of IL‐2 receptor antagonists to reduce delayed graft function following renal transplantation: a review

Abstract

Delayed graft function (DGF) occurs in approximately 30% of renal transplant patients, and significantly increases risk of long-term graft loss. This article reviews the potential for use of interleukin-2 receptor (IL-2R) antagonists to reduce the burden of DGF. IL-2R antagonists decrease incidence of acute rejection without increasing risk of cytomegalovirus infection or malignancy, and show equivalent efficacy to lymphocyte-depleting antibody agents in standard risk patients with immediate graft function. The nephrotoxicity associated with calcineurin inhibitors (CNIs) has led to use of delayed or low-dose CNI regimens with induction therapy in patients with DGF. In this setting, use of an IL-2R antagonist with mycophenolate mofetil and steroids with delayed cyclosporine appears to be associated with a low incidence of biopsy-proven rejection and comparable renal function to patients with immediate function. Additionally, there is intriguing evidence to suggests that IL-2R antagonists may reduce risk of DGF occurring. A number of large-scale and smaller studies have reported a trend to reduced incidence of DGF or improved early renal function using IL-2R antagonists compared with placebo, although data are not entirely consistent. In conclusion, the ability of IL-2R antagonists to reduce acute rejection with no additional safety concerns makes them an attractive option for patients with DGF.

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

“…Prior to the discovery of therapeutic antibodies, IL-2 signaling was prevented by corticosteroids, cyclosporine (via calcineurin inhibition), and rapamycin (through the mTOR pathway) (Hardinger et al 2004;Ponticelli 2005;Geissler et al 2008). The current best therapies for acute rejection prophylaxis include the anti-IL-2Ra therapeutic antibodies dadizumab (Zenapax; HoffmannLa Roche) and basiliximab (Simulect; Novartis) (Church 2003;Vincenti et al 2004;Sandrini 2005;McKeage and McCormack 2010). These agents act through a combination of direct ligand: receptor blockade, receptor down regulation (triggering removal of IL-2Ra from the cell surface without signaling), and antibodydependent cell-mediated cytotoxicity (ADCC) through activation and recognition by NK cells.…”

The efficacy and safety of daclizumab and its potential role in the treatment of multiple sclerosis

“…Since its approval for the prevention of graft rejection more than 15 years ago it has been used in more than 50,000 transplant recipients and has shown a favorable AE profile [Sandrini, 2005]. However, the potentially serious infections, skin reactions, liver abnormalities or autoimmune phenomena in several body organs that were reported in recent clinical trials may restrict its future use to patients with active RRMS as a second line therapy if approved by the regulatory authorities.…”

Biothérapies : vers une deuxième révolution ?

“…Cependant, toutes les indications des biothérapies ne pourront être abordées dans ce dossier thématique et nous avons choisi de nous focaliser sur les maladies hématologiques, auto-immunes et inflammatoires chroniques. D'autres indications ne doivent pas pour autant être minimisées et pourraient faire l'objet de mises au point dans les prochains numéros de la revue : les indications des Ac monoclonaux en cardiologie dans traitement du syndrome coronaire aigu ; en oncologie où les Ac anti-HER2 (trastuzumab) [1] ou l'antivascular endothelial growth factor (VEGF) (bevacizumab) [2] occupent une place de plus en plus importante dans le traitement du cancer du sein ou du cancer du rein et du colon mé tastatique au foie, respectivement ; en transplantation ou les anti-CD25 (basiliximab) [3] et les anti-CD3 sont devenus incontournables dans le traitement du rejet de greffe et/ou de la ré action du greffon contre l'hô te ; en neurologie où plusieurs Ac monoclonaux anti-inté grine (natalizumab), mais aussi alemtuzumab, rituximab, and daclizumab sont prometteurs dans le traitement de la sclé rose en plaques [4].…”