Chicago—In allosensitized patients with end-stage renal disease (ESRD), the efficacy of rituximab for desensitizing and enabling kidney transplantation is limited; tissue B-cell depletion is incomplete. Robert R. Redfield III, MD, and colleagues recently conducted an open-label phase 1b study to test the hypothesis that obinutuzumab may be more effective for desensitization than rituximab. Obinutuzumab is a glycoengineered type 2 anti-CD20 monoclonal antibody that displays increased in vitro and in vivo B-cell depletion compared with rituximab.
The study was designed to examine the safety, pharmacokinetics, and pharmacodynamics of obinutuzumab in hypersensitized patients with ESRD who were awaiting kidney transplantation. Results were reported during a poster session at the 2017 American Transplant Congress in a poster titled Emerging Safety and Tolerability of Obinutuzumab, a Type 2 Anti-CD20 Monoclonal Antibody for the Desensitization of Renal Transplant Candidates.
Patients were assigned to one of two groups: cohort one (n=5) received one infusion of 1000 mg obinutuzumab followed by high-dose intravenous immunoglobulin (IVIG) on days 22 and 43; cohort two (n=20) received two infusions of 1000 mg obinutuzumab followed by high-dose IVIG on days 22 and 43. Nine patients received a total of three infusions; the third dose occurred at the time of kidney transplantation (n=5) or at week 24 (n=4). Conventional flow cytometry (FC) and high-sensitivity FC were used to monitor peripheral blood B-cell counts. A central laboratory was used to analyze anti-human leukocyte antibodies (anti-HLA). When the last patients reached 14 weeks after the final obinutuzumab infusion, a safety and tolerability data cut was taken.
Twenty-three of the 25 patients were women. Mean age was 50 years, mean waitlist time was 5.5 years, and calculated reactive antibody values were 91. One patient in cohort two withdrew because kidney transplantation occurred before administration of the second dose of obinutuzumab.
At week 3, 24 of the remaining 24 patients and 22 of the 24 displayed B cells at or below the lower limit of quantification by FC and high-sensitivity FC. Obinutuzumab was well tolerated. Manageable grade 1 and 2 infusion-related reactions were the most common adverse events; the reactions did not prevent completion of the obinutuzumab infusions. Seven of the 25 patients had serious adverse events, all of which were infections that resolved with standard of care treatment.
Of the 24 patients who completed the protocol, seven have received a kidney transplant to date. Ongoing analysis of treatment effects on anti-HLA alloantibodies is occurring.
In conclusion, the researchers said, “Exposure to obinutuzumab resulted in substantial peripheral B-cell depletion at both dose levels. Emerging experience with obinutuzumab indicates acceptable tolerability in patients with end-stage renal disease undergoing desensitization.”
Source: Redfield R, Jordan S, Schindler T, et al. Emerging safety and tolerability of obinutuzumab, a type 2 anti-CD20 monoclonal antibody for the desensitization of renal transplant candidates. Abstract of a poster presented at the 2017 American Transplant Congress, May 1, 2017, Chicago, Illinois.