Background: Rituximab has limited efficacy for desensitizing allosensitized patients (pts) with end-stage renal disease (ESRD) and enabling kidney transplantation (KTx), however, tissue B-cell depletion is incomplete. We hypothesized that obinutuzumab (Obi), a glycoengineered type 2 anti-CD20 monoclonal antibody that displays increased in vitro and in vivo B-cell depletion compared with rituximab, may be more effective for desensitization.

Methods: Safety, pharmacokinetics and pharmacodynamics of Obi in hypersensitized pts with ESRD awaiting KTx were assessed in an open-label Phase 1b study. Two cohorts of pts received 1 (day 1; cohort 1; n=5) or 2 (day 1, 15; cohort 2; n=20) infusions of 1000 mg Obi followed by high-dose IVIG on days 22 & 43. Nine pts received a total of 3 infusions with the 3^rd dose occurring at the time of KTx (n=5) or at week 24 (n=4). Peripheral blood B-cell counts were monitored by conventional flow cytometry (FC) and high-sensitivity FC (HSFC). Anti-HLA antibody levels were analyzed at a central laboratory. A safety and tolerability data cut was taken when the last pt reached 14 weeks post last Obi infusion.

Results: Most (23/25) pts were women, aged 50 ± 9.4 years, with mean waitlist time of 5.5 ± 2.8 years and calculated panel reactive antibody values of 91 ± 15%. One pt in cohort 2 withdrew because KTx occurred prior to administration of the 2^nd dose of Obi. At week 3, 24/24 pts and 21/24 pts displayed B cells ≤ lower limit of quantitation by FC (LLOQ=20 cells/ul) & HSFC (LLOQ=0.441 cells/ul), respectively. Obi appeared well tolerated. The most frequent adverse events (AEs) were grade 1 & 2 infusion-related reactions (15/25 pts) that were manageable and did not prevent the completion of Obi infusion(s). 7/25 pts experienced 10 serious AEs; all were infections which resolved with standard of care treatment. 7/24 pts have been transplanted to date. Analysis of treatment effects on anti-HLA alloantibodies is ongoing.

Conclusion: Exposure to Obi resulted in substantial peripheral B-cell depletion at both dose levels. Emerging experience with Obi indicates acceptable tolerability in pts with ESRD undergoing desensitization.

CITATION INFORMATION: Redfield R, Jordan S, Schindler T, Tran H, Looney C, Green C, Morimoto A, Rajwanshi R, Cascino M, Brunetta P, Borie D. Emerging Safety and Tolerability of Obinutuzumab, a Type 2 Anti-CD20 Monoclonal Antibody for the Desensitization of Renal Transplant Candidates. Am J Transplant. 2017;17 (suppl 3).

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