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Methods for diagnosing and treating inflammatory bowel disease

A technique for gastroenteritis, patients, used in the field of diagnosis and treatment of inflammatory bowel disease

Inactive Publication Date: 2018-06-08
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This trial and error often involves considerable risk and discomfort for the patient in order to find the most effective therapy

Method used

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  • Methods for diagnosing and treating inflammatory bowel disease
  • Methods for diagnosing and treating inflammatory bowel disease
  • Methods for diagnosing and treating inflammatory bowel disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0356] Phase II, Randomized, Double-Blind, Placebo-Controlled Study and Open-Label Extension Study to Evaluate the Efficacy and Safety of rhuMAbβ7 (etrolizumab) in Patients with Moderate-to-Severe Ulcerative Colitis

[0357] Clinical Study Description

[0358] rhuMAbβ7 (etrolizumab) Description

[0359] rhuMAbβ7 (etrolizumab) is a humanized monoclonal antibody based on human IgG1 subclass III V H , κ subtype-IV L Consensus sequence, and specificity against the β7 subunit of integrin heterodimers. see Figure 1A and B. It has been shown to bind α4β7 with high affinity (K of about 116 pM d ) and αEβ7 (K about 1800pM d ).

[0360] This recombinant antibody has two heavy chains (446 residues) and two light chains (214 residues) covalently linked by interchain and intrachain disulfide bonds typical of IgGl antibodies. For the studies described here, it was produced in Chinese Hamster Ovary (CHO) cells. The molecular weight of the intact aglycosylated rhuMAbβ7 molecule is a...

Embodiment 2

[0389] Example 2 - Predictive Biomarker Research and Analysis

[0390] The effect of rhuMAbβ7 on peripheral blood lymphocytes in patients with ulcerative colitis (UC) was assessed. The number of CD3+ lymphocytes and lymphocytes committed to the Treg or Th17 lineage was quantified by measuring epigenetic activation of the CD3, FoxP3 and IL-17 loci. Epigenetic activation at all three loci has previously been shown to correlate with this immune cell content. Notably, a distinct pattern of epigenetic activation within the FoxP3 gene was shown exclusively in Treg cells but not in FoxP3-positive effector T cells.

[0391]Analysis in 42 anti-TNF-naïve (TNF-naive) and 62 anti-TNF-experienced (TNF-experienced) patients from a placebo-controlled Phase II study of rhuMAbβ7 in patients with moderate-to-severe UC biomarker data. Immune cell content in peripheral blood samples from healthy controls and UC patients was determined by measuring the presence of epigenetic activation at each ...

Embodiment 3

[0400] Example 3 - Predictive Biomarker Analysis in Bowel Biopsies

[0401] Bowel biopsies were collected from study participants during flexible sigmoidoscopy / total colonoscopy at the screening visit (up to 4 weeks prior to treatment). Biopsies were taken from the most inflamed colonic region within 10-40 cm of the outer anal border. Avoid biopsies within necrotic areas of ulcerated mucosa or at suture sites in patients who have previously undergone colectomy. Biopsies were placed in tissue RNA stabilization buffer (RNAlater, Qiagen, cat# 76104) and shipped frozen. Upon receipt, genomic DNA was isolated from intestinal biopsies using the DNeasy Blood and Tissue Kit (Qiagen) according to the manufacturer's protocol.

[0402] Immune cell content in biopsies from patients with ulcerative colitis from a Phase II clinical study was determined by measuring the presence of epigenetic activation at each locus relative to the epigenetic activation of the GAPDH locus determining tota...

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Abstract

Biomarkers predictive of responsiveness to integrin beta7 antagonists, including anti-beta7 integrin subunit antibodies, and methods of using such biomarkers are provided. In addition, methods of treating gastrointestinal inflammatory disorders such as inflammatory bowel diseases including ulcerative colitis and Crohn's disease are provided. Also provided are methods of using such predictive biomarkers for the treatment of inflammatory bowel diseases including ulcerative colitis and Crohn's disease.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 62 / 197,293, filed July 27, 2015, and U.S. Provisional Application No. 62 / 241,331, filed October 14, 2015, each of which is hereby for all purposes in its entirety Incorporated by reference. technical field [0003] Biomarkers predictive of reactivity to integrin β7 antagonists, including anti-β7 integrin subunit antibodies, and methods of using such biomarkers are provided. Additionally, methods of treating gastrointestinal inflammatory disorders, such as inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are provided. Also provided are methods of using such predictive biomarkers for the treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. Background technique [0004] Inflammatory bowel disease (IBD) is a chronic inflammatory autoimmune disorder of the gastrointestinal (GI) tract that...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/50
CPCA61P1/04A61P29/00A61P43/00G01N33/505G01N2800/065G01N2800/52
Inventor T·R·蒙塔古特A·柴F·弗
Owner F HOFFMANN LA ROCHE & CO AG
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