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Methods of treating or selecting a treatment for a subject resistant to TNF inhibitor using a nlrp3 antagonist

An antagonist and subject technology, applied in anti-inflammatory agents, antibody medical ingredients, organic active ingredients, etc., can solve problems such as poor systemic bioavailability, low permeability, etc.

Pending Publication Date: 2021-04-13
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

NLRP3 antagonists that are potent in NLRP3-inflammasome-driven cytokine secretion assays in cells but have low permeability in vitro in permeability assays such as the MDCK assay have pharmacokinetics in rats or mice Compounds have poor systemic bioavailability in clinical trials, but high levels in the colon and / or small intestine may be useful therapeutic options for gut-restricted purposes

Method used

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  • Methods of treating or selecting a treatment for a subject resistant to TNF inhibitor using a nlrp3 antagonist
  • Methods of treating or selecting a treatment for a subject resistant to TNF inhibitor using a nlrp3 antagonist
  • Methods of treating or selecting a treatment for a subject resistant to TNF inhibitor using a nlrp3 antagonist

Examples

Experimental program
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example 1

[3804] Example 1. Research

[3805]The CARD8 gene is located within the inflammatory bowel disease (IBD) 6-linked region on chromosome 19. CARD8 interacts with NLRP3 and apoptosis-associated speck-like protein to form a caspase-1 activation complex called the NLRP3 inflammasome. The NLRP3 inflammasome mediates interleukin-1θ production and secretion by processing pro-IL-1θ into mature, secreted IL-1θ. In addition to its role in the inflammasome, CARD8 is also a potent inhibitor of nuclear factor NF-κB. NF-κB activation is critical for pro-IL-1 production. θ Since overproduction of IL-1θ and dysregulation of NF-κB are hallmarks of Crohn's disease, CARD8 is considered as a risk gene for inflammatory bowel disease in this paper. A significant association between CARD8 and Crohn's disease was detected for the minor allele of the non-synonymous single nucleotide polymorphism (SNP) of the C allele at rs2043211 in two UK studies have risk implications. This SNP introduces a prem...

example 2

[3823] Example 2. Treatment of anti-TNFα resistant patients with NLRP3 antagonists

[3824] PLoS One [PLOS ONE] 2009 Nov 24;4(11):e7984 Described in response to corticosteroids and Mucosal biopsies were obtained upon endoscopy in actively inflamed mucosa of patients with ulcerative colitis refractory to immunosuppression and in normal mucosa from control patients. Patients in this study were classified as responders or non-responders for response to infliximab based on endoscopic and histological findings at 4-6 weeks after the first infliximab. Transcriptomic RNA expression levels of these biopsies were obtained by the inventors of the invention disclosed herein from the publicly available Gene Expression Omnibus GSE 16879 (https: / / www.ncbi.nlm.nih.gov / geo / geo2r / ?acc =GSE16879). Expression levels of RNAs encoding NLRP3 and IL-1β were determined based on probe sets 207075_at and 205067_at, respectively, using GEO2R (a tool available on the same website). Surprisingly, it wa...

example 4

[3830] Example 4. Research

[3831] It is proposed that NLRP3 antagonists reverse anti-TNF resistance-induced T cell depletion / apoptosis in biopsy samples from IBD patients whose disease is clinically considered resistant or unresponsive to anti-TNF therapy.

[3832] The study was designed to determine: whether NLRP3 antagonists inhibit inflammasome function and inflammatory activity in cells and biopsy samples from patients with Crohn's disease or ulcerative colitis; Synergy with anti-TNFα therapy in colitis patients.

[3833] A secondary objective of the study was: to determine whether NLRP3 antagonists reduce inflammasome activity in Crohn's disease and ulcer biopsy samples (comparing results in Crohn's disease and ulcerative colitis with those in control patients ); to determine whether NLRP3 antagonists reduce inflammatory cytokine RNA and protein expression in Crohn's disease and ulcerative colitis samples; to determine whether NLRP3 antagonists induce Crohn's disease i...

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Abstract

Provided herein are methods of treating a subject that include administering a therapeutically effective amount of an NLPR3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity and / or expression as compared to a reference level. Provided herein are methods of treating a subject, methods of selecting a treatment for a subject, methods of selecting a subject for treatment, and methods of selecting a subject for participation in a clinical study that include the administration of a therapeutically effective amount of an NLRP3 antagonist. Also provided are methods of treating a subject having resistance to an anti-TNFalpha agent and methods of determining the efficacy of treatment with an anti-TNFalpha agent. Also provided are methods of treating a subject with a combination of an NLRP3 antagonist and an anti-TNFalpha agent.

Description

technical field [0001] The present disclosure relates, in part, to methods of treating a subject comprising administering an NLRP3 antagonist. The present disclosure also relates in part to methods, combinations and compositions for treating TFNα-associated diseases and anti-TNFα resistance in a subject, the methods, combinations and compositions comprising administering an NLRP3 antagonist, an NLRP3 antagonist and an anti-TNFα agent, or a composition comprising an NLRP3 antagonist and an anti-TNFα agent. Background technique [0002] The NLRP3 inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in genetic disorders such as cryopyrin-associated periodic syndrome (CAPS). Hereditary CAPS Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID) have been reported to be associated with NLRP3 Examples of indications associated with gain-of-function muta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/175A61K31/18A61K31/34A61K31/381A61K31/415A61K31/42A61K31/426A61K31/44A61K31/513A61K31/5375A61K31/64A61K31/196A61K31/277A61K31/352A61K31/365A61K31/519A61K45/06A61P1/00A61P29/00A61K39/395
CPCA61K31/18A61K31/175A61K31/64A61K31/34A61K31/42A61K31/381A61K31/426A61K31/44A61K31/5375A61K31/415A61K31/513A61K31/365A61K31/277A61K31/196A61K31/352A61K31/519A61P29/00A61P1/00A61K45/06A61K2300/00C07K16/241C07K2317/76C07K2317/24A61K2039/505Y02A50/30A61K39/3955A61K31/341A61K31/17A61K31/435A61K31/421A61P37/00C07D277/36C07D261/10C07D333/34C07D409/12C07D417/12C07D401/12C07D403/12C12N15/113C12N2310/11C12N2310/12C12N2310/14C12Q1/6827
Inventor L·弗兰基S·古什G·格利克J·卡茨A·W·小奥皮帕里W·鲁什H·M·塞德尔沈东明S·文卡特拉曼D·G·温克勒
Owner NOVARTIS AG
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