title: 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 inhibitory 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 allotransplantation. 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 calcineurin inhibitor (CNI)-low or CNI-free protocols, without the need of steroids. Accumulation of intragraft Tregs suggested the promotion of immunoregulatory mechanisms. Selective CD28 antagonists might become an alternative CNI-sparing strategy to B7 antagonists for kidney transplant recipients.
authors.affiliation: Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche 1064, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France; Effimune SAS, Nantes, France.
authors.forename: N
authors.initials: N
authors.lastname: Poirier
authors.forename: N
authors.initials: N
authors.lastname: Dilek
authors.forename: C
authors.initials: C
authors.lastname: Mary
authors.forename: S
authors.initials: S
authors.lastname: Ville
authors.forename: F
authors.initials: F
authors.lastname: Coulon
authors.forename: J
authors.initials: J
authors.lastname: Branchereau
authors.forename: X
authors.initials: X
authors.lastname: Tillou
authors.forename: V
authors.initials: V
authors.lastname: Charpy
authors.forename: S
authors.initials: S
authors.lastname: Pengam
authors.forename: V
authors.initials: V
authors.lastname: Nerriere-Daguin
authors.forename: J
authors.initials: J
authors.lastname: Hervouet
authors.forename: D
authors.initials: D
authors.lastname: Minault
authors.forename: S
authors.initials: S
authors.lastname: Le Bas-Bernardet
authors.forename: K
authors.initials: K
authors.lastname: Renaudin
authors.forename: B
authors.initials: B
authors.lastname: Vanhove
authors.forename: G
authors.initials: G
authors.lastname: Blancho
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018106:CD28 Antigens / Q000276:immunology*; D065095:Calcineurin Inhibitors / Q000494:pharmacology*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D007114:Immunization; D007124:Immunoenzyme Techniques; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D007165:Immunosuppression Therapy; D007674:Kidney Diseases / Q000276:immunology / Q000601:surgery; D016030:Kidney Transplantation; D010215:Papio; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D018106:CD28 Antigens; D065095:Calcineurin Inhibitors; D007140:Immunoglobulin Fab Fragments; D012333:RNA, Messenger
keywords: alloantibody; animal models: nonhuman primate; basic (laboratory) research/science; costimulation; fusion proteins and monoclonal antibodies: costimulation molecule specific; immunosuppressant; immunosuppression/immune modulation; immunosuppressive regimens; kidney transplantation; minimization/withdrawal; nephrology