**9. Novel immunosuppressive agents**

Given substantially decreased rates of acute rejection secondary to potent induction agents and CNI based maintenance regimens, the focus has shifted away from acute rejection to preserving grafts for the long-term. However, many studies are still focused on short term outcomes and there are very few studies looking at which drugs or combinations thereof offer better long term graft function.

Long term graft preservation may be particularly challenging given the nephrotoxic effects of CNIs on allografts. To address this issue, a number of novel agents are undergoing trials currently as a replacement to CNIs. [73] Several biologic agents and fusion proteins have emerged and unfortunately many of these agents have been discarded after preliminary trials due to their toxicity. In addition there are several trials focusing on tolerogenic protocols to avoid use of long term immunosuppression. Table 4 below summarizes the new agents that are currently undergoing clinical trials. Belatacept discussed below, is a newer biologic agent that has been studied the most extensively.

#### **9.1. Belatacept**

Belatacept is a recombinant fusion protein with an extracellular domain that consists of hu‐ man cytotoxic T lymphocyte antigen-4 (CTLA-4) and the Fc fragment of human IgG. The fu‐ sion protein Belatacept (CTLA-4Ig) blocks the interaction of CD80/86 present on antigen presenting cells (APC), with the CD28 receptor expressed on T cells. CD80/86 are costimula‐ tory molecules that are necessary for providing costimulation and full activation of T-cells, a requirement for T-cell cytokine production and expansion. The most exciting feature of CTLA4Ig is its known ability to generate immune tolerance particularly in animal models of transplantation and autoimmunity. [74, 75] Whether tolerance can be generated in vivo in humans, however remains to be seen.


\*References [77-79]

primary therapy for AMR. [70] In terms of its ability to decrease the levels of donor specific antibodies in sensitized patients and patients with AMR, studies have provided mixed results. [71, 72] Part of this may be secondary to differing conditioning regimens that accompany the use of Bortezomib. Another important finding reported by two studies is the differential responses of early versus late AMR after treatment with Bortezomib, with early AMR re‐

Rejection may be mixed and have both cellular and humoral components. To date, there are no randomized control studies evaluating different therapies for the treatment of mixed rejection. Case series and small studies suggest that choosing a biologic agent that has activity against both T-cell and B-cell activity would be more favorable. Agents that have broad based activity such as Campath or Bortezomib may be better choices, than T-cell directed agents such as rATG. Plasmapharesis and IVIG may also be added therapies, especially if there is the presence of circulating donor specific antibody. Unfortunately, trials evaluating different combinations

Given substantially decreased rates of acute rejection secondary to potent induction agents and CNI based maintenance regimens, the focus has shifted away from acute rejection to preserving grafts for the long-term. However, many studies are still focused on short term outcomes and there are very few studies looking at which drugs or combinations thereof offer

Long term graft preservation may be particularly challenging given the nephrotoxic effects of CNIs on allografts. To address this issue, a number of novel agents are undergoing trials currently as a replacement to CNIs. [73] Several biologic agents and fusion proteins have emerged and unfortunately many of these agents have been discarded after preliminary trials due to their toxicity. In addition there are several trials focusing on tolerogenic protocols to avoid use of long term immunosuppression. Table 4 below summarizes the new agents that are currently undergoing clinical trials. Belatacept discussed below, is a newer biologic agent

Belatacept is a recombinant fusion protein with an extracellular domain that consists of hu‐ man cytotoxic T lymphocyte antigen-4 (CTLA-4) and the Fc fragment of human IgG. The fu‐ sion protein Belatacept (CTLA-4Ig) blocks the interaction of CD80/86 present on antigen presenting cells (APC), with the CD28 receptor expressed on T cells. CD80/86 are costimula‐ tory molecules that are necessary for providing costimulation and full activation of T-cells, a requirement for T-cell cytokine production and expansion. The most exciting feature of CTLA4Ig is its known ability to generate immune tolerance particularly in animal models of

of these therapies or head to head comparison of these biologic agents do not exist.

sponding much better than late. [25]

222 Current Issues and Future Direction in Kidney Transplantation

**8.3. Treatment of mixed rejection**

**9. Novel immunosuppressive agents**

that has been studied the most extensively.

better long term graft function.

**9.1. Belatacept**

#### Table 4 pg. 19 **Table 4.** Novel Immunosuppressive Agents

\**References* 

**[77-79]**

Belatacept is a relatively new agent used in human transplantation with the first report of its use in human renal transplantation in 2005. The focus of clinical investigative trials utilizing belatacept was to provide a new effective maintenance regimen that would allow for the avoidance of the renal and metabolic side effects of chronic CNI use. Studies such as the BENEFIT and BENEFIT-EXT trials demonstrate its efficacy as a maintenance agent in place of calcineurin inhibitors. [76] The three year follow up data of BENEFIT where belatacept was compared to cyclosporine concluded that patient and graft survival were comparable with better GFR in the belatacept arm. There was however increased incidence of acute rejection and early post transplant lymphoproliferative disease in the belatacept group (especially in EBV sero negative patients). For this reason, belatacept use is approved only for patients who are EBV seropositive. The cost and long term need for intravenous administration of the drug appear to be major obstacles for wide spread use of belatacept. Nevertheless, it still provides a valuable alternative to long term CNI use.
