MO1023: Effects of Bortezomib on Complement Fixation and IGM Reactivity in Late Abmr — Results of A Randomized Controlled Trial (The Borteject Trial)

Abstract

Abstract BACKGROUND AND AIMS Late antibody-mediated rejection (ABMR) is a cardinal cause of kidney allograft failure. Currently, there is no proven effective treatment for this type of rejection. In a recent randomized controlled trial, we have reported no meaningful effect of plasma cell-directed treatment using the proteasome inhibitor bortezomib on the clinical course of late ABMR (BORTEJECT trial; ClinicalTrials.gov, NCT01873157; Eskandary et al. J Am Soc Nephrol, 2018; 29: 591). Treatment had also no significant effect on IgG type donor-specific antibody (DSA) patterns, possibly due to rapid reconstitution of the allospecific plasma cell repertoire. To further dissect the impact of bortezomib on donor-specific B cell alloimmunity, we here sought to investigate whether and to what extent bortezomib impacts the dynamics of specific alloreactivity patterns, in particular, the course of IgM type DSA and complement-activating capability of detected DSA. METHOD The BORTEJECT trial was a randomized, placebo-controlled parallel group trial designed to investigate whether two cycles of bortezomib (each cycle: 1.3 mg/m2 intravenously on days 1, 4, 8 and 11) were able to halt the progression of IgG-DSA-positive late ABMR. A total of 44 recipients were randomly assigned to receive bortezomib (n = 21) or placebo (n = 23). In the present re-analysis of biobanked serum samples obtained in the context of the trial, we applied modified single antigen bead assays to assess IgM-DSA and, in addition, complement (C1q) binding. To estimate antibody/complement binding, levels of mean fluorescence intensity (MFI) were recorded. IgM DSA was defined in relation to donor/recipient HLA typing, independently of IgG reactivity patterns. RESULTS At baseline, the complement-fixing capability of the immunodominant IgG DSA did not differ between groups. Thirty of 44 patients had detectable IgM DSA at baseline, and we observed a considerable overlap of IgG and IgM DSA specificities (22/30) without group differences. IgM DSA levels were also similar between groups. Bortezomib treatment did not affect the complement-fixing capability of IgG DSA over time. Similarly, there was no effect on the course of IgM-DSA. There were also no significant differences between groups when analysing percentage changes. CONCLUSION A limited course of bortezomib as a sole treatment strategy may not be sufficient to impact on DSA levels, including the evolution of IgM type DSA and the complement-binding capability of detected alloreactivity patterns. Our study results, which may mirror the lack of clinical efficacy, reinforce the need for the development of innovative new strategies to effectively target plasma cells and halt the progression of ABMR.