The Most Common Cause of Kidney Allograft Failure
Active antibody-mediated rejection (ABMR), especially chronic active antibody-mediated rejection (CABMR), is now recognized as the most common cause of allograft failure after a successful kidney transplant. Active ABMR and CABMR are part of a continuum of injury which, left untreated, results in the loss of the transplanted allograft. The continuum of injury produced by active ABMR is triggered by inflammation following interaction between complement-activating recipient donor -specific antibodies (DSA) and donor human leukocyte antigen expressed on the surface of the transplant vascular endothelium. Active ABMR is the pathological expression of a repetitive pattern of cellular injury and repair. Regardless of how the process is initiated, this ongoing injury eventually manifests as CABMR with its hallmark chronic tissue injury pathology (i.e., transplant glomerulopathy) and loss of functional renal mass that leads to a decline in renal function.
In kidney transplant recipients with CABMR, a progressive decline in renal function is, by definition, on the pathway to graft loss. Numerous studies in kidney transplant recipients, and specifically in post-transplant patients with ABMR, have shown that progressive renal function decline (as measured by estimated glomerular filtration rate (eGFR)) is significantly correlated with graft loss and patient survival [1-6]. Indeed, measures of renal function (e.g., serum creatinine or eGFR) are commonly used in clinical practice to make decisions on the need and timing of re-initiating dialysis in kidney transplant recipients with imminent graft loss.
Although effective treatment of acute cellular rejections has led to high short-term survival of kidney allografts (i.e., >95% in the first year post-transplant), long term graft survival has not improved. Death-censored graft failure rates beyond the first year have remained relatively unchanged since the late 1980s, and by 10 years, 20%–30% of all kidney allografts will have failed . Current standard of care anti-rejection treatments target cellular-mediated (i.e., T cell mediated rejection) processes and do not affect the humoral-mediated rejection process in CABMR.
Currently, there are no approved or effective treatments for active ABMR, including CABMR. The Kidney Disease: Improving Global Outcomes 2009 guideline  recognizes the lack of good quality data and suggests the use of one or more of the following alternatives, with or without corticosteroids, to treat acute humoral rejections due to DSA: plasma exchange (PLEX); intravenous immunoglobulin (IVIG); anti-CD20 antibody; and lymphocyte-depleting antibody. Recent systematic reviews of treatments for ABMR have shown that the situation remains unchanged, even with novel agents targeting B cells, plasma cells and the complement system [9,10]. In the RITUX ERAH study, there was no early or late (up to 5 years) benefit with rituximab (an anti-CD20 monoclonal antibody) administered with IVIG, PLEX and corticosteroids in kidney transplant recipients with early acute ABMR [11,12]. More specifically, no evidence of efficacy was seen in studies in CABMR with eculizumab (a complement inhibitor), bortezomib (a proteasome inhibitor), IVIG, rituximab and PLEX [13-16].
In summary, the current treatments commonly being used for the treatment of CABMR are not evidenced-based. Considering the cost and potential for serious toxicity with the current treatments, this highlights the need for well-designed randomized controlled studies to investigate the safety and efficacy of any new drugs for the treatment of CABMR – a serious and rare condition with an unmet clinical need. Promising signals of efficacy have been seen with an anti-IL-6 approach .
Interleukin-6: A Key Player in Antibody-Mediated Rejection (ABMR)
IL-6 appears to be a critical cytokine involved in ABMR. IL-6 promotes the development and maturation of B-cells to plasma cells that produce donor-specific antibodies (DSA) targeting the allograft. These DSA cause antibody-mediated injury to the allograft via direct activation of endothelial cells, complement-dependent cytotoxicity and/or antibody-dependent cellular cytotoxicity. Furthermore, IL-6 shapes the T cell immune response resulting in promotion of long-lived pro inflammatory T cells (e.g., follicular T helper cells (Tfh), T helper 17 cells (Th17), T helper 1 cells (Th1), and T helper 2 cells (Th2) and inhibition of immune regulatory T cells (Treg) that promote immune tolerance. Data from clinical studies using the anti-IL-6R mAb tocilizumab suggest the importance of inhibiting IL-6/IL-6R interactions in treatment of ABMR (Choi et al. Am J Transplant. 2017 Sep;17(9):2381-2389).
Clazakizumab: A Potent and Long-Acting IL-6 Antagonist
Clazakizumab is a genetically engineered humanized IgG1 monoclonal antibody that binds to human IL-6 with low-picomolar affinity. Using multiple assays for signaling and cellular functions in response to IL-6 alone (to measure classical signaling) and a combination of IL-6 and sIL-6R (to measure trans-signaling), it was demonstrated that clazakizumab is a potent and full antagonist of IL-6 induced signaling as measured by phosphorylation of signal transducer and activator of transcription 3 (STAT3), as well as cellular functions such as cell proliferation, differentiation, activation, B cell production of immunoglobulins, and hepatocyte production of acute phase proteins (CRP and fibrinogen). In addition, clazakizumab is shown to be a competitive antagonist of IL-6-induced cell proliferation. This in vitro pharmacological profile supports the potential of clazakizumab to impact multiple immune and non-immune cellular processes that are central to the pathogenesis of ABMR in kidney transplant recipients.
Vitaeris is initiating a Phase 3 clinical study to further evaluate the role of IL-6 blockade, using clazakizumab as a means to preserve renal function and prevent renal allograft loss from antibody mediated rejection.
Click here for more information about the clinical study.