期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 16, 期 4, 页码 1266-1275出版社
WILEY
DOI: 10.1111/ajt.13557
关键词
clinical research; practice; basic (laboratory) research; science; immunobiology; kidney transplantation; nephrology; alloantibody; B cell biology; desensitization; immunosuppressant; fusion proteins and monoclonal antibodies: B cell specific
B cell-activation factor (BAFF) is critical for B cell maturation. Inhibition of BAFF represents an appealing target for desensitization of sensitized end-stage renal disease (ESRD) patients. We conducted a Phase 2a, single-arm, open-label exploratory study investigating the effect of tabalumab (BAFF inhibitor) in patients with ESRD and calculated panel reactive antibodies (cPRAs) >50%. The treatment period duration was 24 weeks. Eighteen patients received tabalumab, at doses of 240-mg subcutaneous (SC) at Week 0 followed by 120-mg SC monthly for 5 additional months. Patients were followed for an additional 52 weeks. Immunopharmacologic effects were characterized through analysis of blood for HLA antibodies, BAFF concentrations, immunoglobulins, T and B cell subsets, as well as pre- and posttreatment tonsil and bone marrow biopsies. Significant reductions in cPRAs were observed at Weeks 16 (p=0.043) and 36 (p=0.004); however, absolute reductions were small (<5%). Expected pharmacologic changes in B cell subsets and immunoglobulin reductions were observed. Two tabalumab-related serious adverse events occurred (pneumonia, worsening of peripheral neuropathy), while the most common other adverse events were injection-site pain and hypotension. Three patients received matched deceased donor transplants during follow-up. Treatment with a BAFF inhibitor resulted in statistically significant, but not clinically meaningful reduction in the cPRA from baseline (NCT01200290, Clinicaltrials.gov). Treatment with a B cell-activating factor inhibitor in highly sensitized end-stage kidney disease patients awaiting kidney transplant produces pharmacodynamic effects but does not lead to clinically meaningful reduction in calculated panel reactive antibodies.
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