FR104, an Antagonist Anti-CD28 Monovalent Fab' Antibody, Prevents Alloimmunization and Allows Calcineurin Inhibitor Minimization in Nonhuman Primate Renal Allograft

Abstract : Selective targeting of CD28 might represent an effective immunomodulation strategy by preventing T cell costimulation, while favoring coinhibition since inhib-itory signals transmitted through CTLA-4; PD-L1 and B7 would not be affected. We previously showed in vitro and in vivo that anti-CD28 antagonists suppress effector T cells while enhancing regulatory T cell (Treg) suppression and immune tolerance. Here, we evaluate FR104, a novel antagonist pegylated anti-CD28 Fab' antibody fragment, in nonhuman primate renal allo-transplantation. FR104, in association with low doses of tacrolimus or with rapamycin in a steroid-free therapy, prevents acute rejection and alloantibody development and prolongs allograft survival. However , when FR104 was associated with mycophenolate mofetil and steroids, half of the recipients rejected their grafts prematurely. Finally, we observed an accumulation of Helios-negative Tregs in the blood and within the graft after FR104 therapy, confirmed by Treg-specific demethylated region DNA analysis. In conclusion , FR104 reinforces immunosuppression in calci-neurin inhibitor (CNI)-low or CNI-free protocols, without the need of steroids. Accumulation of intra-graft Tregs suggested the promotion of immunoregu-latory mechanisms. Selective CD28 antagonists might become an alternative CNI-sparing strategy to B7 antagonists for kidney transplant recipients.
Document type :
Journal articles
Complete list of metadatas

Cited literature [65 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-02148443
Contributor : Ana Paula Dutra Azevedo <>
Submitted on : Wednesday, June 5, 2019 - 2:57:29 PM
Last modification on : Thursday, June 6, 2019 - 1:27:06 AM

File

 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document

Identifiers

Collections

Citation

N. Poirier, N. Dilek, C. Mary, S. Ville, F. Coulon, et al.. FR104, an Antagonist Anti-CD28 Monovalent Fab' Antibody, Prevents Alloimmunization and Allows Calcineurin Inhibitor Minimization in Nonhuman Primate Renal Allograft. American Journal of Transplantation, Wiley, 2015, 15 (1), pp.88-100. ⟨10.1111/ajt.12964⟩. ⟨inserm-02148443⟩

Share

Metrics

Record views

31