Immunomodulatory activity of humanized anti–IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes
- 19 December 2019
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 4 (24)
- https://doi.org/10.1172/jci.insight.126054
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 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.Funding Information
- Pfizer Inc (Pfizer Inc)
This publication has 35 references indexed in Scilit:
- IL-7 signaling and CD127 receptor regulation in the control of T cell homeostasisSeminars in Immunology, 2012
- Anti–IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell functionProceedings of the National Academy of Sciences of the United States of America, 2012
- IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cellsProceedings of the National Academy of Sciences of the United States of America, 2012
- A CD8+ T cell transcription signature predicts prognosis in autoimmune diseaseNature Medicine, 2010
- IL-7 Is Essential for Homeostatic Control of T Cell Metabolism In VivoThe Journal of Immunology, 2010
- T Cell Receptor-Dependent Regulation of Lipid Rafts Controls Naive CD8+ T Cell HomeostasisImmunity, 2010
- The molecular signature of CD8+ T cells undergoing deletional toleranceBlood, 2009
- CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunityProceedings of the National Academy of Sciences of the United States of America, 2008
- Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral InfectionImmunity, 2007
- Interleukin 7 Regulates the Survival and Generation of Memory CD4 CellsThe Journal of Experimental Medicine, 2003