2. Academic Validation
  3. TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate renal allograft survival

TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate renal allograft survival

  • Am J Transplant. 2023 Aug;23(8):1171-1181. doi: 10.1016/j.ajt.2023.03.022.
Grace Lassiter 1,  Ryo Otsuka 1,  Takayuki Hirose 1,  Ivy Rosales 2,  Ahmad Karadagi 1,  Toshihide Tomosugi 1,  Abbas Dehnadi 1,  Hang Lee 1,  Robert B Colvin 2,  Jason Baardsnes 3,  Anna Moraitis 3,  Emma E Smith 3,  Zahida Ali 4,  Phil Berhe 4,  Andrew Mulder 5,  Bernd Meibohm 6,  Bruce Daugherty 7,  Siobhan Fogarty 7,  Richard N Pierson 1,  Seth Lederman 7,  Tatsuo Kawai 8
Affiliations

Affiliations

  • 1 Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 2 Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 3 National Research Council, Montréal, Quebec H4P 2R2, Canada.
  • 4 Charles River Laboratories, Skokie, Illinois, USA.
  • 5 Charles River Laboratories, Mattawan, Michigan, USA.
  • 6 College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennesse, USA.
  • 7 Tonix Pharmaceuticals, Inc, Chatham, New Jersey, USA.
  • 8 Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: tkawai@mgh.harvard.edu.
PMID: 37019335 DOI: 10.1016/j.ajt.2023.03.022
Abstract

The blockade of the CD154-CD40 pathway with anti-CD154 monoclonal antibody has been a promising immunomodulatory approach to prevent allograft rejection. However, clinical trials of immunoglobulin G1 antibodies targeting this pathway revealed thrombogenic properties, which were subsequently shown to be mediated by crystallizable fragment (Fc)-gamma receptor IIa-dependent platelet activation. To prevent thromboembolic complications, an immunoglobulin G4 anti-CD154 monoclonal antibody, TNX-1500, which retains the fragment antigen binding region of ruplizumab (humanized 5c8, BG9588), was modified by protein engineering to decrease Fc binding to Fc-gamma Receptor IIa while retaining certain Other effector functions and pharmacokinetics comparable with natural antibodies. Here, we report that TNX-1500 treatment is not associated with platelet activation in vitro and consistently inhibits kidney allograft rejection in vivo without clinical or histologic evidence of prothrombotic phenomena. We conclude that TNX-1500 retains efficacy similar to that of 5c8 to prevent kidney allograft rejection while avoiding previously identified pathway-associated thromboembolic complications.

Keywords

costimulation blockade; immunosuppression; kidney transplantation; nonhuman primates.

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