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. CascinoPaul Brunetta, Dominic Borie

Research output: Contribution to journalArticle

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).

Original languageEnglish (US)
JournalAmerican Journal of Transplantation
DOIs
StatePublished - Jan 1 2019

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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  • Cite this

    Redfield, R. R., Jordan, S. C., Busque, S., Vincenti, F., Woodle, E. S., Desai, N., Reed, E. F., Tremblay, S., Zachary, A. A., Vo, A. A., Formica, R., Schindler, T., Tran, H., Looney, C., Jamois, C., Green, C., Morimoto, A., Rajwanshi, R., Schroeder, A., ... Borie, D. (2019). Safety, pharmacokinetics, and pharmacodynamic activity of obinutuzumab, a type 2 anti-CD20 monoclonal antibody for the desensitization of candidates for renal transplant. American Journal of Transplantation. https://doi.org/10.1111/ajt.15514