Costimulation Blockade in Kidney Transplantation

Abstract

In the setting of solid-organ transplantation, calcineurin inhibitor (CNI)-based therapy remains the cornerstone of immunosuppression. However, long-term use of CNIs is associated with some degree of nephrotoxicity. This has led to exploring the blockade of some costimulation pathways as an efficient immunosuppressive tool instead of using CNIs. The only agent already in clinical use and approved by the health authorities for kidney transplant patients is belatacept (Nulojix), a fusion protein that interferes with cytotoxic T lymphocyte-associated protein 4. Belatacept has been demonstrated to be as efficient as cyclosporine-based immunosuppression and is associated with significantly better renal function, that is, no nephrotoxicity. However, in the immediate posttransplant period, significantly more mild/moderate episodes of acute rejection have been reported, favored by the fact that cytotoxic T lymphocyte-associated protein pathway has an inhibitory effect on the alloimmune response; thereby its inhibition is detrimental in this regard. This has led to the development of antibodies that target CD28. The most advanced is FR104, it has shown promise in nonhuman primate models of autoimmune diseases and allotransplantation. In addition, research into blocking the CD40-CD154 pathway is underway. A phase II study testing ASK1240, that is, anti-CD40 antibody has been completed, and the results are pending.

Selective Costimulation Blockade With Antagonist Anti-CD28 Therapeutics in Transplantation

“…Like current co-stimulation inhibitors, as demonstrated in primates, agents blocking CD28 might also constitute the basis of a CNI-free maintenance therapy, while reducing the rejection risk that has been attributed to the use of belatacept. 45…”

Recent advances in kidney transplantation: a viewpoint from the Descartes advisory board*

“…The approval of belatacept in 2011 demonstrated the potential of a biological non-nephrotoxic maintenance immunosuppression by blocking co-stimulatory signals [ 41 , 42 ]. For the first time since the introduction of cyclosporine, a new immunosuppressant showed an improvement in long-term graft survival.…”

The 2017 IXA Presidential Lecture: Recent developments in xenotransplantation

“…The most successful immunosuppressive protocols for xenotransplantation generally include some form of T cell costimulation blockade, by interfering with: (i) the CD28/B7 interaction using CTLA4‐Ig (belatacept) and/or (ii) the CD40/CD154 interaction using anti‐CD40 or anti‐CD154 monoclonal antibodies. Belatacept is approved for clinical solid organ transplantation, and anti‐CD40 is the subject of phase 2 clinical trials in renal transplantation . “High dose” anti‐CD40 was a key component of the protocol used to achieve long‐term cardiac xenograft survival, although some evidence suggests that anti‐CD154 may be more effective than anti‐CD40, at least in the preclinical islet model .…”