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Kidney Transplantation: Desensitization and other complications

Wednesday September 16, 2020 - 14:30 to 15:15

Room: Channel 6

480.2 Clazakizumab (anti-IL-6) induces FoxP3+ Tregs in highly HLA sensitized patients receiving HLAi kidney transplantation (NCT03380962)

Stanley Jordan, United States

Director, Nephrology & Transplant Immunology, Medical Director, Kidney Transplant Program
Division of Nephrology/Kidney Transplant
Cedars Sinai Medical Center

Biography

Director, Nephrology Transplant Immunology Medical Director, Kidney Transplant Program Cedars-Sinai Medical Center and Professor of Pediatrics & Medicine David Geffen School of Medicine Los Angeles. Dr. Jordan in recognised internationally for his 3 decades of research focussing on the immunology of antibody rejection and development of novel immune modulatory therapies to combat this condition. Dr. Jordan has extensive experience with desensitization for incompatible kidney transplantation and has an active clinical trials programme examining novel therapies for desensitization and treatment of antibody-mediated rejection. He has also published novel clinical trials using complement inhibitors to prevent delayed graft function in renal allografts. Dr. Jordan and his work have been recognized by his peers and include his being the recipient of the National Kidney Foundation “Gift of Life Award” and the Distinguished Alumni Award from the University of North Carolina Chapel Hill. He was honoured with the inaugural Cedars-Sinai Prize for Research in Scientific Medicine (PRISM),conceived to recognize outstanding scientific and medical breakthroughs, the Pioneer in Medicine Award (also from Cedars-Sinai), the Award for Outstanding Achievement in Transplantation from the Transplantation Society, the Jean Hamburger Award for outstanding research in nephrology from the International Society of Nephrology and the Senior Achievement Award in Clinical Transplantation from the American Society of Transplantation. In 2020 Dr. Jordan received the Mayo Soley Award for outstanding clinical research and mentorship from the Western Society of Clinical Investigation.

Abstract

Clazakizumab (anti-IL-6) induces FoxP3+ Tregs in highly HLA sensitized patients receiving HLAi kidney transplantation (NCT03380962)

Stanley Jordan1, Shili Ge2, Nori Ammerman1, Mieko Toyoda2, Edmund Huang1, Alice Peng1, Reiad Najjar1, Supreet Sethi1, Summer Williamson1, Kate Myers1, Kathlyn Lim1, Jua Choi1, Ashley A. Vo1.

1Kidney Transplant, Cedars Sinai Medical Center, Los Angeles, CA, United States; 2Transplant Immunology Laboratory, Cedars Sinai Medical Center, Los Angeles, CA, United States

Introduction: Interleukin-6 is an important inflammatory cytokine which also acts as a growth factor for B-cells, plasma cells and Th17 cells. IL-6 also inhibits FoxP3+ Treg cells.  These considerations suggest blocking IL-6 may be an important method to reduce inflammation and Th17 mediated injury in kidney allografts.
Patients & Methods: Clazakizumab (Vitaeris Inc.) is a humanized monoclonal antibody aimed at the cytokine IL-6. As part of a phase I/II trial of clazakizumab for desensitization, HLA sensitized patients received anti-IL-6, 25mg SC monthly X 6 doses with monitoring of HLA antibody levels and Tregs. Patients were treated pre- and post-transplant with anti-IL-6. Transplanted patients received monthly claza 25mg SC starting 5-7 days post-transplant for 12M.  Tregs were determined by flow cytometry as CD4+,CD25+,CD127dim,FoxP3+ cell populations in CD4+ cells. Determinations were made at baseline, at transplantation and day 180 post-transplant.
Results: Nine patients were transplanted. All patients had previous transplants; 78% had cPRA 99-100%, 67% were B-cell FCMX+ and class II DSA+ @ time of transplant. Mean MFI for HLA cI & cII were: pre-desensitization vs. post claza:  cI 13062±3123 vs. 8585±4597 (p=0.05) and cII 13519±2966 vs. 8344±4836 (p =0.03). All DSA+ patients were negative by day 180 post-transplant. Mean Treg values at baseline v. at transplant did not differ (3.2+1.09% v.3.5+1.75%,p=NS). However, were significantly different at day 180 post-transplant (3.2+1.09% v.3.5+1.75% v. 12.6+9.3%, p=0.008)(Figure 1).
Conclusions: Clazakizumab desensitization reduced HLA cI/cII antibodies and allowed 9/10 highly sensitized patients to receive transplants. In addition, a dramatic increase in Treg cells at day 180 post-transplant was seen while patients were still on anti-IL-6 therapy suggesting that anti-IL-6 may induce CD4+ T-cells toward a Treg profile. This may have therapeutic implications for modifying baseline immunosuppression post-transplant.

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