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Serological markers of inflammatory bowel disease phenotype and disease progression

a inflammatory bowel disease and serological marker technology, applied in the field of serological markers of inflammatory bowel disease phenotype and disease progression, can solve the problems of limiting the ability to predict clinical disease behavior and outcome, difficult diagnosis of ibds, and substantial morbidity

Inactive Publication Date: 2010-10-07
DENSON LEE A +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention is about biological markers and methods for diagnosing and predicting inflammatory bowel diseases. The invention provides biological markers, such as anti-GM-CSF antibodies, that can be used to diagnose and predict the behavior of inflammatory bowel diseases, particularly Crohn's disease. The invention also provides methods for predicting the severity of inflammatory bowel diseases and selecting appropriate therapeutic treatments. The invention also includes kits and immunassays for detecting anti-GM-CSF antibodies. Overall, the invention provides tools for better diagnosis and treatment of inflammatory bowel diseases."

Problems solved by technology

IBDs can be difficult to diagnose, a diagnosis being obtained only after extensive, costly, and often invasive procedures have been performed.
A diagnosis of IC limits the ability to predict clinical disease behavior and outcome following surgery, and prevents patients with refractory disease from entering into clinical trials of new agents.
IBD causes substantial morbidity including frequent hospitalizations and surgeries, and longstanding disease is complicated by cancer (Hanauer S. B. 2006).
However, sustained remissions have not been observed in more than fifty percent of individuals with any new biologic agent.
As the effectiveness of any one agent is typically on the order of 50% to 80%, this leads to a substantial number of patients receiving a series of ineffective agents, with attendant side effects, before an effective regimen is identified.
However, these markers have not proven effective in definitively characterizing IBD patients as CD or UC, and have not been able to predict with sufficient accuracy which patients are most likely to require surgery for the condition.
Thus, these results demonstrate that these markers are not sufficiently sensitive to be used as effective screening tools.
IBD patients further have variable risk of needing surgery to treat the disease.
Current standard clinical approaches are not able to further reduce the number of diagnoses of IC, or to predict which patients will be most likely to progress to surgery.
However, the magnitude of the serological response did not predict the need for 6-MP or infliximab.
A limitation of this approach is the substantial number of patients who experience disease progression and require surgery who are sero-negative for these markers.
Current biomarkers have failed to be effectively used to provide diagnostic tests for classifying, characterizing or predicting the outcome of inflammatory bowel diseases.
In particular, current biomarkers have not been efficacious in distinguishing among the various subtypes of inflammatory bowel diseases.

Method used

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  • Serological markers of inflammatory bowel disease phenotype and disease progression
  • Serological markers of inflammatory bowel disease phenotype and disease progression

Examples

Experimental program
Comparison scheme
Effect test

example i

Determining Anti-GM-CSF Antibody Activity for Classification of Subtypes

[0100]GM-CSF concentration in whole blood or serum samples obtained from a patient suspected of having an inflammatory bowel disease is determined using the methods as described in Uchida, et al. Blood, 2004, incorporated herein by reference, and described herein.

[0101]Anti-GM-CSF antibodies are assayed using serum samples that are either immediately obtained or previously collected and stored at—70° C. until analysis. Anti-GM-CSF antibody concentration of a serum sample from an individual of interest is then measured. The serum sample is diluted 1:100, 1:1000 and 1:3000 with phosphate buffered saline (PBS) containing 1% bovine serum albumin and 0.1% Tween 20. Separate 50 μl aliquots of diluted serum and the affinity-purified anti-GM-CSF antibody isolated from the serum of patients with pulmonary alveolar proteinosis as a standard (0-50 ng / ml) were incubated at room temperature for 40 minutes in ELISA plates pre...

example ii

Anti-GM-CSF Concentration as a Predictor of Disease Behavior

[0102]The methods of Example 1 are carried out essentially as described above. Following performance of the above-described methods, the values obtained from the assay are then used to classify the individual as either having colonic, or ileal or ileo-colonic. Values greater than or equal to about 2 mcg / ml indicate that the disease behavior is less likely to be only colonic (L2), less likely to be non-stricuring, non-penetrating (B1), and more likely to be treated with a surgery. Assessment of the presence or absence of the CARD 15 mutation is not necessary for this determination.

example iii

Determining CD11b Stimulation Index for Classification of Subtypes

[0103]The CD11b Stimulation Index on neutrophils from whole blood samples obtained from an individual suspected of having an inflammatory bowel disease is determined using the methods as described in Uchida, et al. NEJM, 2007, incorporated herein by reference, and described herein. Briefly, this assay is performed using whole blood samples from IBD patients or healthy controls in the absence or presence of stimulation with exogenously added GM-CSF and then cell surface CD11b is quantified on neutrophils (and / or also on monocytes and eosinophils) is then measured by flow cytometry. Neutrophils can be identified with the high expression level of CD16 determined by fluorescein isothiocyanate (FITC)-conjugated anti-CD16 antibody. Monocytes can be determined APC-conjugated anti-CD14 antibody. Eosinophils can be determined moderate expression of CD16 and specific cell size and complexity. This assay provides a method to qua...

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Abstract

Disclosed are novel biomarkers and methods related to diagnostic tests for the detection and characterization of inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis. In particular, the instant invention relates to novel biomarkers and methods of using such biomarkers to predict disease behavior and severity, to differentiate among disease types, and to optimize selection of treatment options in individuals suspected of having an inflammatory bowel disease.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Patent Application Ser. No. 60 / 909,153, which was filed on Mar. 30, 2007, the entirety of which is incorporated herein by reference for all purposes.BACKGROUND OF THE INVENTION[0002]The incidence of the Inflammatory Bowel Diseases (IBD), Crohn's Disease (CD) and Ulcerative Colitis (UC) has increased dramatically over the past four decades with approximately five million individuals affected in North America and Europe. While therapeutic options have increased over the past decade, the ability to classify subtypes of IBDs, predict disease progression and behavior, and target newer biologic therapies to specific subgroups of patients has lagged behind. This has led to an empiric step-up approach to therapy, in which increasingly more potent agents are offered until an effective regimen is identified.[0003]The inflammatory bowel diseases are believed to be caused by a complex interaction b...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): G01N33/53
CPCG01N33/6863G01N2333/535G01N33/68G01N2800/50G01N2800/065A61K38/193C07K16/241C07K2317/21C07K2317/24C07K2317/76G01N33/686
Inventor DENSON, LEE A.TRAPNELL, BRUCE COLSTONUCHIDA, KANJI
Owner DENSON LEE A
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