Integrin-Disrupting Molecules for Tie2 Activation

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Solution Overview

Problem

Current therapies for diseases associated with excessive vascular growth and instability, such as wet age-related macular degeneration and cancer, face challenges in effectively targeting the angiopoietin-Tie pathway due to its complex agonistic and antagonistic activities, which are not fully understood.

Innovation Solution

Pharmaceutical compositions that activate the Tie2 pathway by disrupting αβ integrin heterodimers, using molecules like AXT107, which convert Ang2 from an antagonist to an agonist, thereby strengthening endothelial cell tight junctions and inhibiting vascular leak.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If the angiopoietin-Tie pathway is targeted for treating vascular diseases, then therapeutic efficacy against excessive vascular growth and instability is improved, but the complexity of the pathway with alternating agonistic and antagonistic activities creates uncertainty in treatment outcomes

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidpathway complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention changes the molecular state of Ang2 by disrupting the αβ-integrin heterodimer, converting it from an antagonist to an agonist of Tie2. This parameter change in the molecular interaction state resolves the uncertainty of pathway activity and ensures reliable therapeutic efficacy against vascular diseases.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The αβ-integrin heterodimer acts as an intermediary that normally prevents Tie2 activation by Ang2. By disrupting this intermediary complex, the invention enables direct agonistic interaction between Ang2 and Tie2, simplifying the pathway's functional state and improving treatment reliability.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Object-affected harmful factors

If Ang2 is used to activate Tie2, then vascular permeability increases and vascular instability occurs, but blocking Tie2 activation fails to provide effective therapy due to incomplete understanding of agonistic and antagonistic mechanisms

Engineering Contradiction:

Improvevascular permeabilityVSAvoidmechanism understanding

Core Design Contradiction:

Object-affected harmful factorsVSDifficulty of detecting and measuring

Solution Approach 1:

The invention converts the harmful effect of Ang2 (increased vascular permeability when acting as antagonist) into a beneficial effect by disrupting the αβ-integrin heterodimer. This conversion transforms Ang2 into a Tie2 agonist that stabilizes endothelial junctions and reduces vascular permeability, turning a harmful pathway activation into a therapeutic benefit.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Reliability

If integrin heterodimers are disrupted to activate Tie2, then Tie2 activation is enhanced and vascular stability is improved, but the mechanism of alternation between agonistic and antagonistic activities remains incompletely understood

Engineering Contradiction:

ImproveTie2 activationVSAvoidmechanism understanding

Core Design Contradiction:

ReliabilityVSLoss of information

Solution Approach 1:

The invention extracts the αβ-integrin heterodimer from the regulatory complex that controls Ang2's agonistic/antagonistic switching. By removing this regulatory intermediary through disruption, Tie2 activation is enhanced and stabilized, while the complexity of the switching mechanism is effectively bypassed rather than fully elucidated.

Inventive Principle:

Principle #2Taking out (Extraction)

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

The solution effectively treats excessive vascular growth and instability by enhancing Tie2 activation, reducing vascular permeability, and stabilizing endothelial cell junctions, offering potential therapeutic benefits for various diseases including wet age-related macular degeneration and cancer.

Implementation Method 1

The pharmaceutical agents in accordance with this disclosure are selected for their ability to activate the Tie2 pathway through the disruption of αβ integrin heterodimers

Methodology Applied

Scientific EffectHeterodimer disruption:

Implementation Method 2

the integrin-disrupting molecule converts Ang2 from an antagonist to a strong agonist of Tie2

Methodology Applied

Scientific EffectAntagonist to agonist conversion:

Implementation Method 3

assaying changes in phosphorylation or activity of Tie1 and/or Tie2 or of signaling molecules associated with Tie1 and/or Tie2

Methodology Applied

Scientific EffectPhosphorylation:

Data Source

PatentUS11674959B2Methods for identifying and preparing pharmaceutical agents for activating Tie1 and/or Tie2 receptors

Publication Date: 2023.06.13 OPTANOVA PHARMA LLC

AI summary

The present invention in various aspects and embodiments involves pharmaceutical compositions prepared by contacting a candidate α- or β-integrin-binding molecule, or panel thereof, with an integrin heterodimer, and quantifying heterodimer disruption by the candidate molecule. An integrin-binding molecule, or derivative thereof, that disrupts the integrin heterodimer is selected and is formulated into a pharmaceutical composition for administration to a subject, e.g., who has a disease or disorder related to abnormal vascularization.