A Randomized Clinical Trial of Anti–IL-6 Antibody Clazakizumab in Late Antibody-Mediated Kidney Transplant Rejection
Authors: Doberer Konstantin , Duerr Michael , Halloran Philip F. , Eskandary Farsad , Budde Klemens , Regele Heinz , Reeve Jeff , Borski Anita , Kozakowski Nicolas , Reindl-Schwaighofer Roman , Waiser Johannes , Lachmann Nils , Schranz Sabine , Firbas Christa , Mühlbacher Jakob , Gelbenegger Georg , Perkmann Thomas , Wahrmann Markus , Kainz Alexander , Ristl Robin , Halleck Fabian , Bond Gregor , Chong Edward , Jilma Bernd , Böhmig Georg A. 
Published: December 2020

Significance Statement
There is no proven effective treatment for a major cause of graft failure, late antibody-mediated rejection, but IL-6, a cytokine known to promote B cell immunity, may be a promising therapeutic target. The authors describe the results of a phase 2 randomized clinical trial involving 20 patients, designed to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of an anti–IL-6 antibody, clazakizumab, versus placebo in late antibody-mediated rejection. Although the occurrence of serious infections and diverticulitis presented important safety signals, clazakizumab was associated with an early decrease in donor-specific antibody levels, modulated antibody-mediated rejection activity, and slowed the decline of renal function. Preliminary efficacy results suggest a potentially beneficial effect of clazakizumab and may therefore support the design of larger trials with a longer duration of follow-up.

Background
Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy.

Methods
We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti–IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab.

Results
Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (−0.96; 95% confidence interval [95% CI], −1.96 to 0.03 versus −2.43; 95% CI, −3.40 to −1.46 ml/min per 1.73 m2 per month, respectively, P=0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab.

Conclusions
Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.