TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate cardiac allograft survival.
alloantibody
anti-CD154 monoclonal antibody
cardiac allograft survival
costimulation pathway
heart transplantation
nonhuman primate
Journal
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
ISSN: 1600-6143
Titre abrégé: Am J Transplant
Pays: United States
ID NLM: 100968638
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
20
02
2023
revised:
16
03
2023
accepted:
29
03
2023
pmc-release:
01
08
2024
medline:
29
9
2023
pubmed:
9
4
2023
entrez:
8
4
2023
Statut:
ppublish
Résumé
Blockade of the CD40/CD154 T cell costimulation pathway is a promising approach to supplement or replace current clinical immunosuppression in solid organ transplantation. We evaluated the tolerability and activity of a novel humanized anti-CD154 monoclonal antibody, TNX-1500 (TNX), in a nonhuman primate heterotopic cardiac allogeneic (allo) transplant model. TNX-1500 contains a rupluzimab fragment antigen-binding region and an immunoglobin G4 crystallizable fragment region engineered to reduce binding to the crystallizable fragment gamma receptor IIa and associated risks of thrombosis. Recipients were treated for 6 months with standard-dose TNX (sTNX) monotherapy, low-dose TNX monotherapy (loTNX), or loTNX with mycophenolate mofetil (MMF) (loTNX + MMF). Results were compared with historical data using chimeric humanized 5c8 monotherapy dosed as for loTNX but discontinued at 3 months. Median survival time was similar for humanized 5c8 and both loTNX groups, but significantly longer with sTNX (>265 days) than with loTNX (99 days) or loTNX + MMF (88 days) (P < 0.05 for both comparisons against sTNX). Standard-dose TNX prevented antidonor alloantibody elaboration, inhibited chronic rejection, and was associated with a significantly reduced effector T cells/regulatory T cells ratio relative to loTNX with MMF. No thrombotic complications were observed. This study demonstrated that TNX was well tolerated, prolongs allograft survival, and prevents alloantibody production and cardiac allograft vasculopathy in a stringent preclinical nonhuman primate heart allotransplant model.
Identifiants
pubmed: 37030662
pii: S1600-6135(23)00396-9
doi: 10.1016/j.ajt.2023.03.025
pmc: PMC10524282
mid: NIHMS1902572
pii:
doi:
Substances chimiques
Antibodies, Monoclonal
0
CD40 Ligand
147205-72-9
Antibodies, Monoclonal, Humanized
0
Isoantibodies
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1182-1193Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL158504
Pays : United States
Informations de copyright
Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. All rights reserved.
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