Ang2-Selective Tie2 Receptor Mutations for Vascular Protection

Solution Overview

Problem

Current inhibitors of angiopoietin-2 (Ang2) fail to discriminate between Ang2 and its protective ligand Ang1, leading to unintended suppression of Ang1's protective effects, which are crucial for vascular health.

Innovation Solution

A modified angiopoietin receptor, specifically a variant of the Tie2 ectodomain with specific mutations such as F161I, ΔR167, and ΔH168, is developed to preferentially bind Ang2 over Ang1, allowing for targeted inhibition of Ang2's damaging effects while preserving Ang1's protective functions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Object-affected harmful factors

If a ligand trap is designed to bind Ang2, then Ang2 inhibition is achieved, but Ang1 binding is also blocked causing loss of protective effects

Engineering Contradiction:

ImproveAng2-mediated vessel remodeling and inflammationVSAvoidLoss of Ang1 protective effects

Core Design Contradiction:

Object-affected harmful factorsVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by introducing specific point mutations (F161I, ΔR167, ΔH168) at the ligand binding interface of the Tie2 receptor ectodomain. These localized changes modify the binding pocket's chemical and physical properties to create selective affinity for Ang2 over Ang1, thereby achieving differential binding characteristics that preserve Ang1's protective functions while blocking Ang2's harmful effects

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by altering the amino acid sequence parameters of the Tie2 ectodomain through site-directed mutagenesis. The specific mutations change the binding parameters (affinity, selectivity) of the receptor for different ligands, transforming it from a non-selective binder to an Ang2-preferential binder while maintaining physiological relevance

Inventive Principle:

Principle #35Parameter changes

2Quantity of substance

If the Tie2 receptor is used as a ligand trap, then Ang2 binding capacity is high, but selectivity for Ang2 over Ang1 is low

Engineering Contradiction:

ImproveBinding capacity for Ang2VSAvoidSelectivity between Ang2 and Ang1

Core Design Contradiction:

Quantity of substanceVSMeasurement precision

Solution Approach 1:

The patent applies local quality by introducing specific point mutations (F161I, ΔR167, ΔH168) at the ligand binding interface of the Tie2 receptor ectodomain. These localized changes modify the binding pocket's chemical and physical properties to create selective affinity for Ang2 over Ang1, thereby achieving differential binding characteristics that preserve Ang1's protective functions while blocking Ang2's harmful effects

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by altering the amino acid sequence parameters of the Tie2 ectodomain through site-directed mutagenesis. The specific mutations change the binding parameters (affinity, selectivity) of the receptor for different ligands, transforming it from a non-selective binder to an Ang2-preferential binder while maintaining physiological relevance

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS10882895B2Nucleic acid encoding angiopoietin-2 specific Tie2 receptor

Publication Date: 2021.01.05 UNITED KINGDOM RESEARCH AND INNOVATION

AI summary

In one aspect, provided herein is a polypeptide comprising a modified angiopoietin receptor or fragment thereof, wherein the polypeptide binds preferentially to angiopoietin-2 compared to angiopoeitin-1. Nucleic acid sequences encoding the polypeptide, as well as pharmaceutical uses of the polypeptide in treating diseases such as cancer and inflammation are also provided.