TY - JOUR AU - Herold, Kevan C. AU - Bucktrout, Samantha L. AU - Wang, Xiao AU - Bode, Bruce W. AU - Gitelman, Stephen E. AU - Gottlieb, Peter A. AU - Hughes, Jing AU - Joh, Tenshang AU - McGill, Janet B. AU - Pettus, Jeremy H. AU - Potluri, Shobha AU - Schatz, Desmond AU - Shannon, Megan AU - Udata, Chandrasekhar AU - Wong, Gilbert AU - Levisetti, Matteo AU - Ganguly, Bishu J. AU - Garzone, Pamela D. AU - , T1 - Immunomodulatory activity of humanized anti–IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes PY - 2019/12/19/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.126054 VL - 4 IS - 24 UR - https://doi.org/10.1172/jci.insight.126054 PB - The American Society for Clinical Investigation ER -