Kevan C Herold1,2, Samantha L Bucktrout3, Xiao Wang3, Bruce W Bode4, Stephen E Gitelman5,6, Peter A Gottlieb7,8,9, Jing Hughes10, Tenshang Joh11, Janet B McGill10, Jeremy H Pettus12, Shobha Potluri3, Desmond Schatz13, Megan Shannon11, Chandrasekhar Udata11, Gilbert Wong3, Matteo Levisetti3, Bishu J Ganguly3, Pamela D Garzone3. 1. Department of Immunobiology and. 2. Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA. 3. Rinat, Pfizer Inc., South San Francisco, California, USA. 4. Atlanta Diabetes Associates Research, Atlanta, Georgia, USA. 5. Department of Pediatrics and. 6. Diabetes Center, UCSF, San Francisco, California, USA. 7. Department of Pediatrics. 8. Department of Medicine, and. 9. Barbara Davis Diabetes Center, University of Colorado School of Medicine Anschutz Medical Campus, Anschutz, Colorado, USA. 10. Division of Endocrinology, Metabolism and Lipid Research, John T. Milliken Department of Internal Medicine, Washington University School of Medicine in Saint Louis, Saint Louis, Missouri, USA. 11. Worldwide R&D, Pfizer Inc., San Diego, California, USA. 12. Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA. 13. Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA.
Abstract
BACKGROUND: The cytokine IL-7 is critical for T cell development and function. We performed a Phase Ib study in patients with type 1 diabetes (T1D) to evaluate how blockade of IL-7 would affect immune cells and relevant clinical responses. METHODS:Thirty-seven subjects with T1D received s.c. RN168, a monoclonal antibody that blocks the IL -7 receptorα (IL7Rα) in a dose-escalating study. RESULTS: Between 90% and 100% IL-7R occupancy and near-complete inhibition of pSTAT5 was observed at doses of RN168 1 mg/kg every other week (Q2wk) and greater. There was a significant decline in CD4+ and CD8+ effector and central memory T cells and CD4+ naive cells, but there were fewer effects on CD8+ naive T cells. The ratios of Tregs to CD4+ or CD8+ effector and central memory T cells versus baseline were increased. RNA sequencing analysis showed downmodulation of genes associated with activation, survival, and differentiation of T cells. Expression of the antiapoptotic protein Bcl-2 was reduced. The majority of treatment-emergent adverse events (TEAEs) were mild and not treatment related. Four subjects became anti-EBV IgG+ after RN168, and 2 had symptoms of active infection. The immunologic response to tetanus toxoid was preserved at doses of 1 and 3 mg/kg Q2wk but reduced at higher doses. CONCLUSIONS: This trial shows that, at dosages of 1-3 mg/kg, RN168 selectively inhibits the survival and activity of memory T cells while preserving naive T cells and Tregs. These immunologic effects may serve to eliminate pathologic T cells in autoimmune diseases. TRIAL REGISTRATION: NCT02038764. FUNDING: Pfizer Inc.
RCT Entities:
BACKGROUND: The cytokine IL-7 is critical for T cell development and function. We performed a Phase Ib study in patients with type 1 diabetes (T1D) to evaluate how blockade of IL-7 would affect immune cells and relevant clinical responses. METHODS: Thirty-seven subjects with T1D received s.c. RN168, a monoclonal antibody that blocks the IL -7 receptor α (IL7Rα) in a dose-escalating study. RESULTS: Between 90% and 100% IL-7R occupancy and near-complete inhibition of pSTAT5 was observed at doses of RN168 1 mg/kg every other week (Q2wk) and greater. There was a significant decline in CD4+ and CD8+ effector and central memory T cells and CD4+ naive cells, but there were fewer effects on CD8+ naive T cells. The ratios of Tregs to CD4+ or CD8+ effector and central memory T cells versus baseline were increased. RNA sequencing analysis showed downmodulation of genes associated with activation, survival, and differentiation of T cells. Expression of the antiapoptotic protein Bcl-2 was reduced. The majority of treatment-emergent adverse events (TEAEs) were mild and not treatment related. Four subjects became anti-EBV IgG+ after RN168, and 2 had symptoms of active infection. The immunologic response to tetanus toxoid was preserved at doses of 1 and 3 mg/kg Q2wk but reduced at higher doses. CONCLUSIONS: This trial shows that, at dosages of 1-3 mg/kg, RN168 selectively inhibits the survival and activity of memory T cells while preserving naive T cells and Tregs. These immunologic effects may serve to eliminate pathologic T cells in autoimmune diseases. TRIAL REGISTRATION: NCT02038764. FUNDING: Pfizer Inc.
Entities:
Keywords:
Clinical Trials; Diabetes; Immunology; T cells
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