Assessment of Tocilizumab (Anti–Interleukin-6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy in HLA-Sensitized Renal Allograft Recipients

Abstract

Extending the functional integrity of renal allografts is the primary goal of transplant medicine. The development of donor-specific antibodies (DSAs) posttransplantation leads to chronic active antibody-mediated rejection (cAMR) and transplant glomerulopathy (TG), resulting in the majority of graft losses that occur in the United States. This reduces the quality and length of life for patients and increases cost. There are no approved treatments for cAMR. Evidence suggests the proinflammatory cytokine interleukin 6 (IL-6) may play an important role in DSA generation and cAMR. We identified 36 renal transplant patients with cAMR plus DSAs and TG who failed standard of care treatment with IVIg plus rituximab with or without plasma exchange. Patients were offered rescue therapy with the anti-IL-6 receptor monoclonal tocilizumab with monthly infusions and monitored for DSAs and long-term outcomes. Tocilizumab-treated patients demonstrated graft survival and patient survival rates of 80% and 91% at 6 years, respectively. Significant reductions in DSAs and stabilization of renal function were seen at 2 years. No significant adverse events or severe adverse events were seen. Tocilizumab provides good long-term outcomes for patients with cAMR and TG, especially compared with historical published treatments. Inhibition of the IL-6-IL-6 receptor pathway may represent a novel approach to stabilize allograft function and extend patient lives.

Treatment of chronic antibody mediated rejection with intravenous immunoglobulins and rituximab: A multicenter, prospective, randomized, double-blind clinical trial

“…28 Altogether, these data show that the number of trials done at present to treat chronic ABMR is insufficient if we take into consideration that it is one of the main reasons for late graft failure. Finally, tocilizumab, an anti IL6 receptor monoclonal antibody, was evaluated in an open study as a recue therapy for 36 patients with chronic ABMR who did not respond to their standard of care (plasma exchange, IVIG, and RTX).…”

Advances in the immunology of heart transplantation

“…Recently, tocilizumab (TCZ), a first-in-class, humanized, interleukin-6 (IL-6) receptor monoclonal antibody (MAb), was shown to safely and effectively reduce DSA levels in highly sensitized kidney allograft recipients 47 and to improve graft and patient survival in kidney recipients with the most severe form of chronic AMR. 48 In addition, a Streptococcus pyogenes –derived endopeptidase that degrades immunoglobulin G (IgG), thereby inhibiting complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, was shown to reduce or eliminate DSAs, permitting HLA-incompatible renal transplantation in 24 of 25 patients. 49 These novel agents may soon contribute to the prevention/treatment of AMR in heart recipients.…”

The relationship between pathologic lesions of active and chronic antibody-mediated rejection in renal allografts

“…Notably, in the majority of patients, the initial detection of TG by light microscopy, with or without concurrent glomerulitis, occurs ≥1 year posttransplant in recipients of +CM transplants and even later in recipients of conventional allografts 3,15,22,23. A randomized placebo-controlled clinical trial of bortezomib in patients with active ABMR (median 5 years posttransplant; chronic active in 64%), yielded similar negative results,25 although some recent evidence suggests that the decline in graft function in patients with chronic active ABMR can be slowed or even halted (but not reversed) with newer therapeutic agent(s) 26. A randomized placebo-controlled clinical trial of bortezomib in patients with active ABMR (median 5 years posttransplant; chronic active in 64%), yielded similar negative results,25 although some recent evidence suggests that the decline in graft function in patients with chronic active ABMR can be slowed or even halted (but not reversed) with newer therapeutic agent(s) 26.…”

“…Antibody-mediated rejection (ABMR) diagnosis is according to the Banff 2013 criteria 26. Only the initial biopsy from any individual patient who had endarteritis is represented; all DSA-positive patients undergoing a renal allograft biopsy showing endarteritis from 2011 to 2014 are included.…”