Head-to-head study of oxelumab and adalimumab in a mouse model of ulcerative colitis based on NOD/Scid IL2Rγnull mice reconstituted with human peripheral blood mononuclear cells.

Henrika Jodeleit,Thomas Leeuw,Simone Breiteneicher,Paula Winkelmann,Florian Beigel,Roswitha Gropp,Janina Caesar,Matthias Siebeck,Eckart Bartnik,Johannes Stallhofer,Lesca M Holdt,Sebastian Sterz

doi:10.1242/dmm.046995

Abstract

ABSTRACTThis study's aim was to demonstrate that the combination of patient immune profiling and testing in a humanized mouse model of ulcerative colitis (UC) might lead to patient stratification for treatment with oxelumab. First, immunological profiles of UC patients and non-UC donors were analyzed for CD4+ T cells expressing OX40 (CD134; also known as TNFRSF4) and CD14+ monocytes expressing OX40L (CD252; also known as TNFSF4) by flow cytometric analysis. A significant difference was observed between the groups for CD14+ OX40L+ (UC: n=11, 85.44±21.17, mean±s.d.; non-UC: n=5, 30.7±34.92; P=0.02), whereas no significant difference was detected for CD4+ OX40+. CD14+ OX40L+ monocytes were correlated significantly with T helper 1 and 2 cells. Second, NOD/Scid IL2Rγ null mice were reconstituted with peripheral blood mononuclear cells from UC donors exhibiting elevated levels of OX40L, and the efficacy of oxelumab was compared with that of adalimumab. The clinical, colon and histological scores and the serum concentrations of IL-6, IL-1β and glutamic acid were assessed. Treatment with oxelumab or adalimumab resulted in significantly reduced clinical, colon and histological scores, reduced serum concentrations of IL-6 and reduced frequencies of splenic human effector memory T cells and switched B cells. Comparison of the efficacy of adalimumab and oxelumab by orthogonal partial least squares discrimination analysis revealed that oxelumab was slightly superior to adalimumab; however, elevated serum concentrations of glutamic acid suggested ongoing inflammation. These results suggest that oxelumab addresses the pro-inflammatory arm of inflammation while promoting the remodeling arm and that patients exhibiting elevated levels of OX40L might benefit from treatment with oxelumab.

Highlights

OX40 (CD134; known as TNFRSF4) belongs to the family of tumor necrosis factor (TNF) receptors (TNFRs)
Expression of OX40 and OX40L in peripheral blood mononuclear cells (PBMCs) of ulcerative colitis (UC) and non-UC donors Given that OX40 and OX40L expression has been shown to increase in inflamed colons of UC patients (Souza et al, 1999), we analyzed PBMCs of UC patients (n=81) and non-UC donors for frequencies of CD4+ CD134+ cells
Frequencies of CD4+ T cells expressing the early activation marker CD69 were significantly induced in UC patients

Summary

Introduction

OX40 (CD134; known as TNFRSF4) belongs to the family of tumor necrosis factor (TNF) receptors (TNFRs). Expression of OX40 is induced in T cells in response to antigen recognition and other pro-inflammatory factors and is thought to augment antigeninitiated signaling to promote proliferation, differentiation and survival of effector and memory CD4+ and CD8+ T cells (for review, see Webb et al, 2016). Its cognate ligand OX40L (CD252; known as TNFSF4) is expressed on antigen-presenting, endothelial and mast cells (Linton et al, 2003; Jenkins et al, 2007; Kashiwakura et al, 2004; Imura et al, 1996). TNF receptor adaptor factors (TRAFs) mediate the interaction with the PI3K/Akt and NFκB pathway, leading to proliferation, survival and cytokine expression (So and Croft, 2013). It has been suggested that close proximity of T cell receptor (TCR)/CD28 and OX40 signalosomes facilitate co-signaling of both pathways. A clinical study has shown reduced serum IgE levels and reduced numbers of airway eosinophils in response to treatment with oxelumab; no effect was observed on allergeninduced airway responses (Gauvreau et al, 2014)

Methods

Results

Conclusion