Immunomodulatory activity of humanized anti–IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes

RN168 Working Group

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4 Scopus citations

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.

Original languageEnglish (US)
Article numbere126054
JournalJCI Insight
Volume4
Issue number24
DOIs
StatePublished - Dec 5 2019

Bibliographical note

Funding Information:
The authors thank the study subjects and all of those at the study sites who participated in the investigation. Editorial support was provided by Lauren Cerruto and Michael D. Morren of Peloton Advantage, an OPEN Health Company, and was funded by Pfizer Inc. This study was sponsored by Pfizer Inc. See Supplemental Acknowledgments for consortium details.

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