Safety, pharmacokinetics, and pharmacodynamic activity of obinutuzumab, a type 2 anti-CD20 monoclonal antibody for the desensitization of candidates for renal transplant
Robert R Redfield, Stanley C Jordan, Stephan Busque, Flavio Vincenti, E Steve Woodle, Niraj Desai, Elaine F Reed, Simon Tremblay, Andrea A Zachary, Ashley A Vo, Richard Formica, Thomas Schindler, Ha Tran, Caroline Looney, Candice Jamois, Cherie Green, Alyssa Morimoto, Richa Rajwanshi, Aaron Schroeder, Matthew D Cascino, Paul Brunetta, Dominic Borie, Robert R Redfield, Stanley C Jordan, Stephan Busque, Flavio Vincenti, E Steve Woodle, Niraj Desai, Elaine F Reed, Simon Tremblay, Andrea A Zachary, Ashley A Vo, Richard Formica, Thomas Schindler, Ha Tran, Caroline Looney, Candice Jamois, Cherie Green, Alyssa Morimoto, Richa Rajwanshi, Aaron Schroeder, Matthew D Cascino, Paul Brunetta, Dominic Borie
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.
© 2019 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.
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