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

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.

• Authors: Kevan C Herold, Samantha L Bucktrout, Xiao Wang, Bruce W Bode, Stephen E Gitelman, Peter A Gottlieb, Jing Hughes, Tenshang Joh, Janet B McGill, Jeremy H Pettus, Shobha Potluri, Desmond Schatz, Megan Shannon, Chandrasekhar Udata, Gilbert Wong, Matteo Levisetti, Bishu J Ganguly, Pamela D Garzone, RN168 Working Group
• Journal: JCI insight (JCI Insight) Vol. 4 Issue 24 (12 19 2019) ISSN: 2379-3708 [Electronic] United States
• PMID: 31852846 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• IL7 protein, human
• IL7R protein, human
• Interleukin-7
• Interleukin-7 Receptor alpha Subunit
• monoclonal antibody RN168

Topics

• Adult
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Cell Survival (drug effects, immunology)
• Diabetes Mellitus, Type 1 (blood, drug therapy, immunology)
• Dose-Response Relationship, Drug
• Dose-Response Relationship, Immunologic
• Female
• Humans
• Immunologic Memory (drug effects)
• Interleukin-7 (immunology, metabolism)
• Interleukin-7 Receptor alpha Subunit (antagonists & inhibitors, metabolism)
• Male
• Middle Aged
• Signal Transduction (drug effects, immunology)
• Treatment Outcome