Addition of IL-6 receptor blockade to Carfilzomib-based desensitization in a highly sensitized nonhuman primate model

• Type of Material: Article
• Authors: Imran J. Anwar, Duke University; Brian Ezekian, Duke University; Isabel DeLaura, Duke University; Miriam Manook, Duke University; Paul Schroder, Duke University; Janghoon Yoon, Duke University; Verna Curfman, Duke University; Evelyn Branum, Duke University; Julia Messina, Duke University; Melissa Harnois, Duke University; Sallie R. Permar, Duke University; Alton B Farris III, Emory University; Jean Kwun, Duke University; Stuart J. Knechtle, Duke University
• Language: English
• Date: 2022-12
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022 American Society of Transplantation & American Society of Transplant Surgeons.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1111/ajt.17208
• Title of Journal or Parent Work: American Journal of Transplantation
• Volume: 22
• Issue: 4
• Start Page: 1
• End Page: 11
• Grant/Funding Information: Anti-CD4mAb and anti-CD8mAb used in this study was produced and provided by the Non-human Primate Reagent Resource (5R24OD010976, 1U24AI126683).; This work was partially supported by the National Institute of Allergy and infectious Diseases of the National Institutes of Health as part of the NHP Transplantation Tolerance Cooperative Study Group under the U19AI051731 (awarded to S.J.K.). Additionally, this work was supported by PO1AI129859 (awarded to S.R.P) and NIH T32 AI141342-03 (awarded to I.J.A).
• Keywords: sensitization; kidney transplantation; desensitization; carfilzomib; tocilizumab
• Research Categories: Health Sciences, Immunology; Health Sciences, Medicine and Surgery

Abstract

Sensitized patients, those who had prior exposure to foreign HLA antigens, are transplanted at lower rates due to challenges in finding suitable organs. Desensitization strategies have permitted highly sensitized patients to undergo kidney transplantation, albeit with higher rates of rejection. This study assesses targeting plasma cell and IL-6 receptor for desensitization in a sensitized nonhuman primate kidney transplantation model. All animals were sensitized using two sequential skin transplants from maximally MHC-mismatched donors. Carfilzomib/Tocilizumab desensitization (N=6) successfully decreased donor-specific antibody (DSA) titers and prevented expansion of B cells compared to Carfilzomib monotherapy (N=3). Dual desensitization further delayed, but did not prevent humoral rebound, as evidenced by a delayed increase in post-kidney transplant DSA titers. Accordingly, Carfilzomib/Tocilizumab desensitization conferred significant survival advantage over Carfilzomib monotherapy. A trend towards increased T follicular helper cells was also observed in the dual therapy group along the same timeline as increase in DSA and subsequent graft loss. CMV reactivation also occurred in the carfilzomib/tocilizumab group but was prevented with ganciclovir prophylaxis. In accordance with prior studies of Carfilzomib-based dual desensitization strategies, the addition of IL-6 receptor blockade resulted in desensitization with further suppression of post-transplant humoral response compared to Carfilzomib monotherapy.