TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate renal allograft survival.
costimulation blockade
immunosuppression
kidney transplantation
nonhuman primates
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:
08
02
2023
revised:
23
03
2023
accepted:
24
03
2023
pmc-release:
01
08
2024
medline:
14
8
2023
pubmed:
6
4
2023
entrez:
5
4
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37019335
pii: S1600-6135(23)00371-4
doi: 10.1016/j.ajt.2023.03.022
pmc: PMC10527606
mid: NIHMS1905672
pii:
doi:
Substances chimiques
CD40 Ligand
147205-72-9
Antibodies, Monoclonal
0
CD40 Antigens
0
Immunoglobulin G
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1171-1181Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL158504
Pays : United States
Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
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