TL1A Agonist Mucosal Healing IBD

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Solution Overview

Problem

Current treatments for inflammatory bowel disease (IBD) do not effectively promote mucosal healing in the gastrointestinal tract, as they fail to adequately regulate interleukin-22-producing group 3 innate lymphoid cells (ILC3), which are critical for intestinal homeostasis and barrier integrity.

Innovation Solution

The method involves administering compositions that stimulate ILC3 to produce IL-22 by manipulating the function of CX3CR1+ mononuclear phagocytes (MNPs) or using agents like TL1A, which enhances IL-23- and IL-1β-induced production of IL-22 and granulocyte macrophage colony-stimulating factor (GM-CSF), potentially using fecal microbiota to induce these effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments for IBD are administered, then inflammation is targeted, but mucosal healing is not effectively promoted

Engineering Contradiction:

Improvemucosal healing effectivenessVSAvoidinflammation persistence

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent introduces TL1A as an intermediary substance that mediates between the immune system and intestinal epithelium. TL1A binds to DR3 receptors on ILC3 cells, triggering IL-22 production which then acts as a mediator to promote mucosal healing and barrier integrity, resolving the contradiction between inflammation control and healing promotion

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the therapeutic parameter from general anti-inflammatory targeting to specific ILC3 cell activation through TL1A administration. This parameter shift increases IL-22 production levels, which directly promotes mucosal healing while maintaining anti-inflammatory effects, thereby resolving the effectiveness contradiction

Inventive Principle:

Principle #35Parameter changes

2Stability of the object's composition

If ILC3 activation is enhanced to promote mucosal healing, then barrier integrity improves, but treatment complexity increases

Engineering Contradiction:

Improveintestinal barrier integrityVSAvoidtreatment mechanism complexity

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent utilizes the body's own ILC3 cells and IL-22 production mechanism to achieve mucosal healing. By administering TL1A, the treatment harnesses the patient's inherent immune system components rather than introducing complex external mechanisms, thereby improving barrier integrity while maintaining treatment simplicity

Inventive Principle:

Principle #25Self-service

Solution Approach 2:

TL1A serves as a simple intermediary molecule that naturally activates the existing ILC3-IL-22 axis. This approach leverages the body's endogenous healing mechanisms through a single therapeutic agent, avoiding complex multi-component treatments while effectively restoring intestinal barrier function

Inventive Principle:

Principle #24Intermediary (Mediator)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This approach promotes mucosal healing by enhancing IL-22 production, thereby improving intestinal barrier integrity and reducing inflammation in IBD, as demonstrated by increased IL-22 production in both mouse and human models, correlating with exposure to the fecal stream in patients with IBD.

Implementation Method 1

TL1A, which enhances IL-23- and IL-1β-induced production of IL-22 and granulocyte macrophage colony-stimulating factor (GM-CSF) by ILC3

Methodology Applied

Scientific EffectCytokine-receptor binding:

Implementation Method 2

identify the ability of TNF-like ligand 1A (TL1A) produced by MNPs to potently enhance IL-23- and IL-1β-induced production of IL-22

Methodology Applied

Scientific EffectCytokine induction:

Implementation Method 3

Our results reveal a critical role for CX3CR1+ MNPs from both mouse and human tissue in supporting IL-22 induction in ILC3 in vitro and in vivo

Methodology Applied

Scientific EffectCytokine production:

Implementation Method 4

The present method utilizes therapeutic manipulation of CX3CR1+ MNP function and/or events downstream to promote ILC3 production of IL-22

Methodology Applied

Scientific EffectMucosal healing:

Data Source

PatentUS10160805B2Methods of treating inflammatory bowel disease by administering tumor necrosis factor-like ligand 1A or an agonistic death-domain receptor 3 antibody

Publication Date: 2018.12.25 CORNELL UNIVERSITY

AI summary

Methods and compositions for treating inflammatory bowel disease by promoting mucosal healing in the gastrointestinal (GI) tract are encompassed herein. More particularly, methods and compositions described herein relate to agents that activate mononuclear phagocytes (MNPs) in the GI tract and, in turn, regulate the activity of interleukin (IL)-22-producing group 3 innate lymphoid cells (ILC3) in close proximity thereto.