Safety, pharmacokinetics, and pharmacodynamic activity of obinutuzumab, a type 2 anti-CD20 monoclonal antibody for the desensitization of candidates for renal transplant

Abstract

The limited effectiveness of rituximab plus intravenous immunoglobulin (IVIG) in desensitization may be due to incomplete B cell depletion. Obinutuzumab is a type 2 anti-CD20 antibody that induces increased B cell depletion relative to rituximab and may therefore be more effective for desensitization. This open-label phase 1b study assessed the safety, pharmacokinetics, and pharmacodynamics of obinutuzumab in highly sensitized patients with end-stage renal disease. Patients received 1 (day 1, n = 5) or 2 (days 1 and 15; n = 20) infusions of 1000-mg obinutuzumab followed by 2 doses of IVIG on days 22 and 43. Eleven patients received additional obinutuzumab doses at the time of transplant and/or at week 24. The median follow-up duration was 9.4 months. Obinutuzumab was well tolerated, and most adverse events were grade 1-2 in severity. There were 11 serious adverse events (SAEs) in 9 patients (36%); 10 of these SAEs were infections and 4 occurred after kidney transplant. Obinutuzumab plus IVIG resulted in profound peripheral B cell depletion and appeared to reduce B cells in retroperitoneal lymph nodes. Reductions in anti-HLA antibodies, number of unacceptable antigens, and the calculated panel reactive antibody score as centrally assessed using single-antigen bead assay were limited and not clinically meaningful for most patients (NCT02586051).

Keywords: B cell biology; alloantibody; clinical research/practice; clinical trial; immunosuppressant - fusion proteins and monoclonal antibodies: B cell specific; immunosuppression/immune modulation; kidney transplantation/nephrology; pharmacology.

Figure 1

Patient disposition and number of obinutuzumab (Obi) doses. ^aThis patient received 1 obinutuzumab dose before transplant and 1 dose after. ^bThis patient received a transplant at week 1 and was withdrawn from study treatment. ^cThese 5 patients received 2 obinutuzumab doses before transplant and 1 dose after. ^dThis patient received 2 obinutuzumab doses before transplant and 2 doses after

Figure 2

CD19⁺ peripheral B cell counts in patients from cohort 1 and cohort 2 during the desensitization phase. Cell counts are given in number of cells per μL as a function of study days. The lower limit of quantification of the high‐sensitivity flow cytometry assay was 0.441 cells/μL and is indicated with a dashed line. Traces for the 2 patients with detectable antidrug antibodies are marked with an asterisk

Figure 3

CD19⁺ B cell frequency in peritoneal lymph nodes of patients who received a transplant (7 patients, 13 nodes)

Figure 4

Mean percent reduction in MFI and 95% CIs from baseline to week 24 (filled circles) or last valid MFI measurement (open circles); limited to alleles with MFI > 3000 at any time point and baseline or posttreatment MFI > 500. Marker size is proportional to the number of alleles per patient. Mean and 95% CIs were calculated using bootstrapping with bias‐corrected CI. Patients who have received a transplant are encircled in green; patients identified as biological responders by the DASP are boxed. Abbreviations: CI, confidence interval; DASP, desensitization assessment scientific panel; MFI, mean fluorescence intensity

Figure 5

Change in the number of UAs (A, B) and CPRA score (C, D) from baseline to week 24 or last valid MFI measurement. For UAs and CPRA presented in panels B and D, change in acceptability of a given antigen needed not only to surpass the MFI threshold of 3000 but also display a robust change in MFI of 50%. Abbreviations: CFB, change from baseline; CPRA, calculated panel reactive antibody; MFI, mean fluorescence intensity; UA, unacceptable antigen