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

Autor:	Herold KC; Department of Immunobiology and.; Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA., Bucktrout SL; Rinat, Pfizer Inc., South San Francisco, California, USA., Wang X; Rinat, Pfizer Inc., South San Francisco, California, USA., Bode BW; Atlanta Diabetes Associates Research, Atlanta, Georgia, USA., Gitelman SE; Department of Pediatrics and.; Diabetes Center, UCSF, San Francisco, California, USA., Gottlieb PA; Department of Pediatrics.; Department of Medicine, and.; Barbara Davis Diabetes Center, University of Colorado School of Medicine Anschutz Medical Campus, Anschutz, Colorado, USA., Hughes J; 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., Joh T; Worldwide R&D, Pfizer Inc., San Diego, California, USA., McGill JB; 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., Pettus JH; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA., Potluri S; Rinat, Pfizer Inc., South San Francisco, California, USA., Schatz D; Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA., Shannon M; Worldwide R&D, Pfizer Inc., San Diego, California, USA., Udata C; Worldwide R&D, Pfizer Inc., San Diego, California, USA., Wong G; Rinat, Pfizer Inc., South San Francisco, California, USA., Levisetti M; Rinat, Pfizer Inc., South San Francisco, California, USA., Ganguly BJ; Rinat, Pfizer Inc., South San Francisco, California, USA., Garzone PD; Rinat, Pfizer Inc., South San Francisco, California, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2019 Dec 19; Vol. 4 (24). Date of Electronic Publication: 2019 Dec 19.
DOI:	10.1172/jci.insight.126054
Abstrakt:	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.
Databáze:	MEDLINE
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