Biomarkers of therapeutic response in the IL-23 pathway in inflammatory bowel disease

Corinne Cayatte, Barbara Joyce-Shaikh, Felix Vega, Katia Boniface, Jeffrey Grein, Erin Murphy, Wendy M. Blumenschein, Smiley Chen, Maria Christina Malinao, Beth Basham, Robert H. Pierce, Edward P. Bowman, Brent S. McKenzie, Charles O. Elson, William Alvis Faubion, Rene De Waal Malefyt, Robert A. Kastelein, Daniel Cua, Terrill K. McClanahan, Maribel Beaumont

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

OBJECTIVES: Interleukin-23 (IL-23) has emerged as a new therapeutic target for the treatment of inflammatory bowel disease (IBD). As biomarkers of disease state and treatment efficacy are becoming increasingly important in drug development, we sought to identify efficacy biomarkers for anti-IL-23 therapy in Crohn's disease (CD). METHODS: Candidate IL-23 biomarkers, downstream of IL-23 signaling, were identified using shotgun proteomic analysis of feces and colon lavages obtained from a short-term mouse IBD model (anti-CD40 Rag2 -/-) treated preventively with monoclonal antibodies (mAbs) to the IL-23 receptor (IL-23R). The biomarkers were then measured in an IBD T-cell transfer model treated therapeutically with a mAb to IL-23 (p19), confirming their association with IBD. To assess the clinical relevance of these markers, we assessed their concentrations in clinical serum, colon tissue, and feces from CD patients. RESULTS: We identified 57 proteins up or downregulated in diseased animals that returned to control values when the mice were treated with mAbs to IL-23R. Among those, S100A8, S100A9, regenerating protein 3β (REG), REG3γ, lipocalin 2 (LCN2), deleted in malignant tumor 1 (DMBT1), and macrophage migration inhibitory factor (MIF) mRNA levels correlated with disease score and dose titration of mAbs to IL-23R or IL-23(p19). All biomarkers, except DMBT1, were also downregulated after therapeutic administration of mAbs to IL-23(p19) in a T-cell transfer IBD mouse model. In sera from CD patients, we confirmed a significant upregulation of S100A8/A9 (43%), MIF (138%), pancreatitis-associated protein (PAP, human homolog of REG3β/γ; 49%), LCN2 (520%), and CCL20 (1280%), compared with control samples, as well as a significant upregulation of S100A8/A9 (887%), PAP (401%), and LCN2 (783%) in human feces from CD patients compared with normal controls. CONCLUSIONS: These studies identify multiple protein biomarkers downstream of IL-23 that could be valuable tools to assess the efficacy of this new therapeutic agent.

Original languageEnglish (US)
Article numbere10
JournalClinical and Translational Gastroenterology
Volume3
DOIs
StatePublished - 2012

Fingerprint

Interleukin-23
Inflammatory Bowel Diseases
Biomarkers
Crohn Disease
Monoclonal Antibodies
Feces
Therapeutics
Colon
Calgranulin B
Up-Regulation
Down-Regulation
Interleukin Receptors
Macrophage Migration-Inhibitory Factors
T-Lymphocytes
Animal Diseases
Therapeutic Irrigation
Firearms
Serum
Proteomics
Proteins

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Cayatte, C., Joyce-Shaikh, B., Vega, F., Boniface, K., Grein, J., Murphy, E., ... Beaumont, M. (2012). Biomarkers of therapeutic response in the IL-23 pathway in inflammatory bowel disease. Clinical and Translational Gastroenterology, 3, [e10]. https://doi.org/10.1038/ctg.2012.2

Biomarkers of therapeutic response in the IL-23 pathway in inflammatory bowel disease. / Cayatte, Corinne; Joyce-Shaikh, Barbara; Vega, Felix; Boniface, Katia; Grein, Jeffrey; Murphy, Erin; Blumenschein, Wendy M.; Chen, Smiley; Malinao, Maria Christina; Basham, Beth; Pierce, Robert H.; Bowman, Edward P.; McKenzie, Brent S.; Elson, Charles O.; Faubion, William Alvis; Malefyt, Rene De Waal; Kastelein, Robert A.; Cua, Daniel; McClanahan, Terrill K.; Beaumont, Maribel.

In: Clinical and Translational Gastroenterology, Vol. 3, e10, 2012.

Research output: Contribution to journalArticle

Cayatte, C, Joyce-Shaikh, B, Vega, F, Boniface, K, Grein, J, Murphy, E, Blumenschein, WM, Chen, S, Malinao, MC, Basham, B, Pierce, RH, Bowman, EP, McKenzie, BS, Elson, CO, Faubion, WA, Malefyt, RDW, Kastelein, RA, Cua, D, McClanahan, TK & Beaumont, M 2012, 'Biomarkers of therapeutic response in the IL-23 pathway in inflammatory bowel disease', Clinical and Translational Gastroenterology, vol. 3, e10. https://doi.org/10.1038/ctg.2012.2
Cayatte, Corinne ; Joyce-Shaikh, Barbara ; Vega, Felix ; Boniface, Katia ; Grein, Jeffrey ; Murphy, Erin ; Blumenschein, Wendy M. ; Chen, Smiley ; Malinao, Maria Christina ; Basham, Beth ; Pierce, Robert H. ; Bowman, Edward P. ; McKenzie, Brent S. ; Elson, Charles O. ; Faubion, William Alvis ; Malefyt, Rene De Waal ; Kastelein, Robert A. ; Cua, Daniel ; McClanahan, Terrill K. ; Beaumont, Maribel. / Biomarkers of therapeutic response in the IL-23 pathway in inflammatory bowel disease. In: Clinical and Translational Gastroenterology. 2012 ; Vol. 3.
@article{1b933c4c94834659a2a4a72e485f4f02,
title = "Biomarkers of therapeutic response in the IL-23 pathway in inflammatory bowel disease",
abstract = "OBJECTIVES: Interleukin-23 (IL-23) has emerged as a new therapeutic target for the treatment of inflammatory bowel disease (IBD). As biomarkers of disease state and treatment efficacy are becoming increasingly important in drug development, we sought to identify efficacy biomarkers for anti-IL-23 therapy in Crohn's disease (CD). METHODS: Candidate IL-23 biomarkers, downstream of IL-23 signaling, were identified using shotgun proteomic analysis of feces and colon lavages obtained from a short-term mouse IBD model (anti-CD40 Rag2 -/-) treated preventively with monoclonal antibodies (mAbs) to the IL-23 receptor (IL-23R). The biomarkers were then measured in an IBD T-cell transfer model treated therapeutically with a mAb to IL-23 (p19), confirming their association with IBD. To assess the clinical relevance of these markers, we assessed their concentrations in clinical serum, colon tissue, and feces from CD patients. RESULTS: We identified 57 proteins up or downregulated in diseased animals that returned to control values when the mice were treated with mAbs to IL-23R. Among those, S100A8, S100A9, regenerating protein 3β (REG), REG3γ, lipocalin 2 (LCN2), deleted in malignant tumor 1 (DMBT1), and macrophage migration inhibitory factor (MIF) mRNA levels correlated with disease score and dose titration of mAbs to IL-23R or IL-23(p19). All biomarkers, except DMBT1, were also downregulated after therapeutic administration of mAbs to IL-23(p19) in a T-cell transfer IBD mouse model. In sera from CD patients, we confirmed a significant upregulation of S100A8/A9 (43{\%}), MIF (138{\%}), pancreatitis-associated protein (PAP, human homolog of REG3β/γ; 49{\%}), LCN2 (520{\%}), and CCL20 (1280{\%}), compared with control samples, as well as a significant upregulation of S100A8/A9 (887{\%}), PAP (401{\%}), and LCN2 (783{\%}) in human feces from CD patients compared with normal controls. CONCLUSIONS: These studies identify multiple protein biomarkers downstream of IL-23 that could be valuable tools to assess the efficacy of this new therapeutic agent.",
author = "Corinne Cayatte and Barbara Joyce-Shaikh and Felix Vega and Katia Boniface and Jeffrey Grein and Erin Murphy and Blumenschein, {Wendy M.} and Smiley Chen and Malinao, {Maria Christina} and Beth Basham and Pierce, {Robert H.} and Bowman, {Edward P.} and McKenzie, {Brent S.} and Elson, {Charles O.} and Faubion, {William Alvis} and Malefyt, {Rene De Waal} and Kastelein, {Robert A.} and Daniel Cua and McClanahan, {Terrill K.} and Maribel Beaumont",
year = "2012",
doi = "10.1038/ctg.2012.2",
language = "English (US)",
volume = "3",
journal = "Clinical and Translational Gastroenterology",
issn = "2155-384X",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Biomarkers of therapeutic response in the IL-23 pathway in inflammatory bowel disease

AU - Cayatte, Corinne

AU - Joyce-Shaikh, Barbara

AU - Vega, Felix

AU - Boniface, Katia

AU - Grein, Jeffrey

AU - Murphy, Erin

AU - Blumenschein, Wendy M.

AU - Chen, Smiley

AU - Malinao, Maria Christina

AU - Basham, Beth

AU - Pierce, Robert H.

AU - Bowman, Edward P.

AU - McKenzie, Brent S.

AU - Elson, Charles O.

AU - Faubion, William Alvis

AU - Malefyt, Rene De Waal

AU - Kastelein, Robert A.

AU - Cua, Daniel

AU - McClanahan, Terrill K.

AU - Beaumont, Maribel

PY - 2012

Y1 - 2012

N2 - OBJECTIVES: Interleukin-23 (IL-23) has emerged as a new therapeutic target for the treatment of inflammatory bowel disease (IBD). As biomarkers of disease state and treatment efficacy are becoming increasingly important in drug development, we sought to identify efficacy biomarkers for anti-IL-23 therapy in Crohn's disease (CD). METHODS: Candidate IL-23 biomarkers, downstream of IL-23 signaling, were identified using shotgun proteomic analysis of feces and colon lavages obtained from a short-term mouse IBD model (anti-CD40 Rag2 -/-) treated preventively with monoclonal antibodies (mAbs) to the IL-23 receptor (IL-23R). The biomarkers were then measured in an IBD T-cell transfer model treated therapeutically with a mAb to IL-23 (p19), confirming their association with IBD. To assess the clinical relevance of these markers, we assessed their concentrations in clinical serum, colon tissue, and feces from CD patients. RESULTS: We identified 57 proteins up or downregulated in diseased animals that returned to control values when the mice were treated with mAbs to IL-23R. Among those, S100A8, S100A9, regenerating protein 3β (REG), REG3γ, lipocalin 2 (LCN2), deleted in malignant tumor 1 (DMBT1), and macrophage migration inhibitory factor (MIF) mRNA levels correlated with disease score and dose titration of mAbs to IL-23R or IL-23(p19). All biomarkers, except DMBT1, were also downregulated after therapeutic administration of mAbs to IL-23(p19) in a T-cell transfer IBD mouse model. In sera from CD patients, we confirmed a significant upregulation of S100A8/A9 (43%), MIF (138%), pancreatitis-associated protein (PAP, human homolog of REG3β/γ; 49%), LCN2 (520%), and CCL20 (1280%), compared with control samples, as well as a significant upregulation of S100A8/A9 (887%), PAP (401%), and LCN2 (783%) in human feces from CD patients compared with normal controls. CONCLUSIONS: These studies identify multiple protein biomarkers downstream of IL-23 that could be valuable tools to assess the efficacy of this new therapeutic agent.

AB - OBJECTIVES: Interleukin-23 (IL-23) has emerged as a new therapeutic target for the treatment of inflammatory bowel disease (IBD). As biomarkers of disease state and treatment efficacy are becoming increasingly important in drug development, we sought to identify efficacy biomarkers for anti-IL-23 therapy in Crohn's disease (CD). METHODS: Candidate IL-23 biomarkers, downstream of IL-23 signaling, were identified using shotgun proteomic analysis of feces and colon lavages obtained from a short-term mouse IBD model (anti-CD40 Rag2 -/-) treated preventively with monoclonal antibodies (mAbs) to the IL-23 receptor (IL-23R). The biomarkers were then measured in an IBD T-cell transfer model treated therapeutically with a mAb to IL-23 (p19), confirming their association with IBD. To assess the clinical relevance of these markers, we assessed their concentrations in clinical serum, colon tissue, and feces from CD patients. RESULTS: We identified 57 proteins up or downregulated in diseased animals that returned to control values when the mice were treated with mAbs to IL-23R. Among those, S100A8, S100A9, regenerating protein 3β (REG), REG3γ, lipocalin 2 (LCN2), deleted in malignant tumor 1 (DMBT1), and macrophage migration inhibitory factor (MIF) mRNA levels correlated with disease score and dose titration of mAbs to IL-23R or IL-23(p19). All biomarkers, except DMBT1, were also downregulated after therapeutic administration of mAbs to IL-23(p19) in a T-cell transfer IBD mouse model. In sera from CD patients, we confirmed a significant upregulation of S100A8/A9 (43%), MIF (138%), pancreatitis-associated protein (PAP, human homolog of REG3β/γ; 49%), LCN2 (520%), and CCL20 (1280%), compared with control samples, as well as a significant upregulation of S100A8/A9 (887%), PAP (401%), and LCN2 (783%) in human feces from CD patients compared with normal controls. CONCLUSIONS: These studies identify multiple protein biomarkers downstream of IL-23 that could be valuable tools to assess the efficacy of this new therapeutic agent.

UR - http://www.scopus.com/inward/record.url?scp=84861872216&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861872216&partnerID=8YFLogxK

U2 - 10.1038/ctg.2012.2

DO - 10.1038/ctg.2012.2

M3 - Article

C2 - 23238132

AN - SCOPUS:84861872216

VL - 3

JO - Clinical and Translational Gastroenterology

JF - Clinical and Translational Gastroenterology

SN - 2155-384X

M1 - e10

ER -