Sequential Targeting of CD52 and TNF Allows Early Minimization Therapy in Kidney Transplantation: From a Biomarker to Targeting in a Proof-Of-Concept Trial

PLoS One. 2017 Jan 13;12(1):e0169624. doi: 10.1371/journal.pone.0169624. eCollection 2017.

Abstract

Background: There is high medical need for safe long-term immunosuppression monotherapy in kidney transplantation. Selective targeting of post-transplant alloantigen-(re)activated effector-T cells by anti-TNF antibodies after global T cell depletion may allow safe drug minimization, however, it is unsolved what might be the best maintenance monotherapy.

Methods: In this open, prospective observational single-centre trial, 20 primary deceased donor kidney transplant recipients received 2x20 mg Alemtuzumab (d0/d1) followed by 5 mg/kg Infliximab (d2). For 14 days all patients received only tacrolimus, then they were allocated to either receive tacrolimus (TAC, n = 13) or sirolimus (SIR, n = 7) monotherapy, respectively. Protocol biopsies and extensive immune monitoring were performed and patients were followed-up for 60 months.

Results: TAC-monotherapy resulted in excellent graft survival (5yr 92%, 95%CI: 56.6-98.9) and function, normal histology, and no proteinuria. Immune monitoring revealed low intragraft inflammation (urinary IP-10) and hints for the development of operational tolerance signature in the TAC- but not SIR-group. Remarkably, the TAC-monotherapy was successful in all five presensitized (ELISPOT+) patients. However, recruitment into SIR-arm was stopped (after n = 7) because of high incidence of proteinuria and acute/chronic rejection in biopsies. No opportunistic infections occurred during follow-up.

Conclusions: In conclusion, our novel fast-track TAC-monotherapy protocol is likely to be safe and preliminary results indicated an excellent 5-year outcome, however, a full-scale study will be needed to confirm our findings.

Trial registration: EudraCT Number: 2006-003110-18.

Publication types

  • Clinical Trial
  • Observational Study

MeSH terms

  • Adult
  • Antigens, CD
  • Antigens, Neoplasm
  • Biomarkers / metabolism
  • CD52 Antigen
  • Female
  • Gene Expression Profiling
  • Glycoproteins / antagonists & inhibitors*
  • Graft Rejection / drug therapy*
  • Graft Rejection / etiology
  • Humans
  • Immunosuppressive Agents / therapeutic use*
  • Kidney Transplantation / adverse effects*
  • Male
  • Middle Aged
  • Monitoring, Immunologic
  • Prospective Studies
  • Sirolimus / therapeutic use
  • Tacrolimus / therapeutic use
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Young Adult

Substances

  • Antigens, CD
  • Antigens, Neoplasm
  • Biomarkers
  • CD52 Antigen
  • CD52 protein, human
  • Glycoproteins
  • Immunosuppressive Agents
  • Tumor Necrosis Factor-alpha
  • Sirolimus
  • Tacrolimus

Grants and funding

This work was supported by RISET (EU FP6 program) and Bio-DrIM (EU FP7 program). O.V. is the recipient of grants from the Internal Grant Agency of the Ministry of Health of the Czech Republic NT14102-3/2013 and AZV ČR 15-26865A and MH CZ DRO (“Institute for Clinical and Experimental Medicine – IKEM, IN 00023001”). Miltenyi Biotec GmbH provided support in the form of salaries for authors [S.T., S.S.,U.J., B.G.], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of these authors is articulated in the 'author contributions' section.