Receptor occupancy and blocking of STAT5 signaling by an anti-IL-7 receptor antibody in cynomolgus monkeys

被引：14

作者：

Kern, Brent ^{[1
]}

Li, Wenlin ^{[1
]}

Bono, Christine ^{[2
]}

Lee, Li-Fen ^{[3
]}

Kraynov, Eugenia ^{[1
]}

机构：

[1] Pfizer, Pharmacokinet Dynam & Metab, La Jolla, CA USA

[2] Pfizer, Drug Safety Res & Dev, Groton, CT USA

[3] Pfizer, Rinat, Expt Med, San Francisco, CA USA

来源：

CYTOMETRY PART B-CLINICAL CYTOMETRY | 2016年 / 90卷 / 02期

关键词：

receptor occupancy; IL-7; receptor; (IL-7R); pSTAT5; monoclonal antibody; multiple sclerosis; type I diabetes; INTERLEUKIN-7; RECEPTOR; IL-7; GAMMA-CHAIN; T-CELLS; EXPRESSION; ASSOCIATION; CLONING; DIFFERENTIATION; ATR-107; TSLP;

D O I：

10.1002/cyto.b.21247

中图分类号：

R446 [实验室诊断]; R-33 [实验医学、医学实验];

学科分类号：

1001 ;

摘要：

BackgroundInterleukin-7 receptor (IL-7R) is associated with autoimmune disease. Blocking its activation by interleukin-7 (IL-7) with a therapeutic monoclonal antibody may reduce pathogenic T cells and effectively control the autoimmune response in these disorders. MethodsTwo flow cytometry-based assays were developed and implemented to evaluate the interaction between cell surface IL-7R and an anti-IL-7R monoclonal antibody (Ab1). The receptor occupancy assay utilized competing and noncompeting commercial detection antibodies for free and total IL-7R, respectively. STAT5 phosphorylation (pSTAT5) was measured as a proximal biomarker of IL-7R inhibition by Ab1. ResultsMonkeys administered Ab1 had no free IL-7R detectable on the CD3+ T cell surface at 0.25 hours postdose through day 4, in all treatment groups. Ab1 treatment resulted in a significant reduction in total IL-7R, dropping to 53%, 44%, and 55% on day 4 at 0.3, 3, and 30mg/kg, respectively, compared to predose levels. There were treatment-related decreases in the ability of IL-7 to induce STAT5 phosphorylation in both CD4+ and CD8+ T cells in monkey blood samples from all treated animals from 0.25 hours through Day 4 postdose. ConclusionsThe nonclinical receptor occupancy assay was developed and applied to detect free and total IL-7R on the surface of CD3+ T cells in cynomolgus monkeys treated with Ab1. The results showed good correlation with the phosphorylation of STAT5 and serum concentration of Ab1. The approach for IL-7R occupancy and pSTAT5 measurements established in monkeys can be utilized in clinical trials for pharmacokinetic/pharmacodynamic evaluation of Ab1 effect in humans. (c) 2015 International Clinical Cytometry Society

引用

页码：191 / 198

页数：8

共 25 条

[11] TSLP: An epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation [J].

Liu, Yong-Jun ;

Soumelis, Vasilli ;

Watanabe, Norihiko ;

Ito, Tomoki ;

Wang, Yul-Hsi ;

de Waal Malefyt, Rene ;

Omori, Miyuki ;

Zhou, Baohua ;

Ziegler, Steven F. .

ANNUAL REVIEW OF IMMUNOLOGY, 2007, 25 :193-219

[12] Variation in interleukin 7 receptor a chain (IL7R) influences risk of multiple sclerosis [J].

Lundmark, Frida ;

Duvefelt, Kristina ;

Iacobaeus, Ellen ;

Kockum, Ingrid ;

Wallstroem, Erik ;

Khademi, Mohsen ;

Oturai, Annette ;

Ryder, Lars P. ;

Saarela, Janna ;

Harbo, Hanne F. ;

Celius, Elisabeth G. ;

Salter, Hugh ;

Olsson, Tomas ;

Hillert, Jan .

NATURE GENETICS, 2007, 39 (09) :1108-1113

[13]

Maraskovsky E, 1996, J IMMUNOL, V157, P5315

[14] Interleukin-7 receptor expression: intelligent design [J].

Mazzucchelli, Renata ;

Durum, Scott K. .

NATURE REVIEWS IMMUNOLOGY, 2007, 7 (02) :144-154

[15] A CD8+ T cell transcription signature predicts prognosis in autoimmune disease [J].

McKinney, Eoin F. ;

Lyons, Paul A. ;

Carr, Edward J. ;

Hollis, Jane L. ;

Jayne, David R. W. ;

Willcocks, Lisa C. ;

Koukoulaki, Maria ;

Brazma, Alvis ;

Jovanovic, Vojislav ;

Kemeny, D. Michael ;

Pollard, Andrew J. ;

MacAry, Paul A. ;

Chaudhry, Afzal N. ;

Smith, Kenneth G. C. .

NATURE MEDICINE, 2010, 16 (05) :586-U122

[16] Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis [J].

Mells, George F. ;

Floyd, James A. B. ;

Morley, Katherine I. ;

Cordell, Heather J. ;

Franklin, Christopher S. ;

Shin, So-Youn ;

Heneghan, Michael A. ;

Neuberger, James M. ;

Donaldson, Peter T. ;

Day, Darren B. ;

Ducker, Samantha J. ;

Muriithi, Agnes W. ;

Wheater, Elizabeth F. ;

Hammond, Christopher J. ;

Dawwas, Muhammad F. ;

Jones, David E. ;

Peltonen, Leena ;

Alexander, Graeme J. ;

Sandford, Richard N. ;

Anderson, Carl A. .

NATURE GENETICS, 2011, 43 (04) :329-U151

[17]

National Research Council, 2011, GUIDE CARE USE LAB A, DOI DOI 10.17226/12910

[18] INTERLEUKIN-2 RECEPTOR GAMMA-CHAIN - A FUNCTIONAL COMPONENT OF THE INTERLEUKIN-7 RECEPTOR [J].

NOGUCHI, M ;

NAKAMURA, Y ;

RUSSELL, SM ;

ZIEGLER, SF ;

TSANG, M ;

CAO, XQ ;

LEONARD, WJ .

SCIENCE, 1993, 262 (5141) :1877-1880

[19]

PAGE TH, 1993, J IMMUNOL, V151, P4753

[20] Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin [J].

Pandey, A ;

Ozaki, K ;

Baumann, H ;

Levin, SD ;

Puel, A ;

Farr, AG ;

Ziegler, SF ;

Leonard, WJ ;

Lodish, HF .

NATURE IMMUNOLOGY, 2000, 1 (01) :59-64

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