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

• Published in: American journal of transplantation Vol. 15; no. 1; pp. 88 - 100
• Main Authors: Poirier, N., Dilek, N., Mary, C., Ville, S., Coulon, F., Branchereau, J., Tillou, X., Charpy, V., Pengam, S., Nerriere‐Daguin, V., Hervouet, J., Minault, D., Le Bas‐Bernardet, S., Renaudin, K., Vanhove, B., Blancho, G.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2015; Elsevier
• Subjects: alloantibody; animal models: nonhuman primate; Animals; basic (laboratory) research/science; Blotting, Western; Calcineurin Inhibitors - pharmacology; CD28 Antigens - immunology; Cells, Cultured; costimulation; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; fusion proteins and monoclonal antibodies: costimulation molecule specific; Graft Rejection - drug therapy; Graft Rejection - immunology; Graft Survival - drug effects; Graft Survival - immunology; Human health and pathology; Immunization; Immunoenzyme Techniques; Immunoglobulin Fab Fragments - pharmacology; immunosuppressant; Immunosuppression Therapy; immunosuppression/immune modulation; immunosuppressive regimens; Kidney Diseases - immunology; Kidney Diseases - surgery; Kidney Transplantation; Life Sciences; minimization/withdrawal; nephrology; Papio; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; T-Lymphocytes, Regulatory - immunology; Transplantation, Homologous; Transplants & implants; nephrology; fusion proteins and monoclonal antibodies: costimulation molecule specific; costimulation; immunosuppression/immune modulation; minimization/withdrawal; kidney transplantation; alloantibody; immunosuppressant; animal models: nonhuman primate; immunosuppressive regimens; basic (laboratory) research/science
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/ajt.12964

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. This study reports the effect of a novel selective CD28 antagonist that preserves CTLA‐4 immunomodulatory signals in association with CNI‐free or CNI‐low regimen in nonhuman primate kidney allotransplantation.