Abstract

Antibody-mediated rejection (AMR), including chronic AMR (cAMR), causes ~50% of kidney allograft losses each year. Despite attempts to develop well-tolerated and effective therapeutics for the management of AMR, to date, none has obtained FDA approval, thereby highlighting an urgent unmet medical need. Discoveries over the past decade from basic, translational and clinical studies of transplant recipients have provided a foundation for developing novel therapeutic approaches to preventing and treating AMR and cAMR. These interventions are aimed at reducing donor-specific antibody levels, decreasing graft injury and fibrosis, and preserving kidney function. Innovative approaches emerging from basic science findings include targeting interactions between alloreactive T cells and B cells, and depleting alloreactive memory B cells, as well as donor-specific antibody-producing plasmablasts and plasma cells. Therapies aimed at reducing the cytotoxic antibody effector functions mediated by natural killer cells and the complement system, and their associated pro-inflammatory cytokines, are also undergoing evaluation. The complexity of the pathogenesis of AMR and cAMR suggest that multiple approaches will probably be required to treat these disease processes effectively. Definitive answers await results from large, double-blind, multicentre, randomized controlled clinical trials.

Key points

• Understanding the expression pattern of surface antigens — including CD19, CD20 and CD38 — on B cell subsets can guide strategies for using monoclonal antibodies to deplete relevant effector B cell subsets.
• Enhanced understanding of the pleiotropic effects of IL-6–IL-6 receptor signalling in antibody-mediated rejection has led to early trials targeting IL-6R (tocilizumab) or IL-6 (clazakizumab) as potential effective therapies.
• Plasma cell depletion strategies used in the treatment of multiple myeloma, including proteosome inhibition and an anti-CD38 monoclonal antibody (daratumumab)-mediated depletion of plasma cells, are being tested in kidney transplant recipients with chronic antibody-mediated rejection.
• New approaches to targeting antibody effector functions with C1 esterase inhibitor (blocks classical and mannose-binding lectin complement pathways), eculizumab (inhibits terminal complement and membrane-attack complex (MAC) formation), imlifidase (cleaves antibody Fc region) and neonatal Fc receptor monoclonal antibodies (prevent antibody recycling and shorten antibody half-lives) show promise for preventing or treating antibody-mediated rejection.