HGF NK1 Variant Polypeptides for Met Receptor Binding

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Solution Overview

Problem

Current therapeutic agents targeting the Met receptor for cancer treatment face challenges such as limited Met receptor binding affinity, recombinant expression yield, and protein stability, and there is a need for effective molecular imaging agents to visualize Met expression in vivo.

Innovation Solution

Development of polypeptide variants of Hepatocyte Growth Factor (HGF) that form covalently linked dimers with improved Met receptor binding affinity and stability, which can be used in pharmaceutical formulations for therapeutic and diagnostic applications, including tissue regeneration and molecular imaging.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional therapeutic agents are used to target the Met receptor, then cancer treatment is provided, but the Met receptor binding affinity is limited

Engineering Contradiction:

ImproveMet receptor binding affinityVSAvoidtherapeutic efficacy

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent applies parameter changes by modifying the amino acid sequence of HGF variants to optimize Met receptor binding affinity. Specific amino acid substitutions are introduced to enhance the interaction between the variants and the Met receptor, thereby improving therapeutic efficacy while maintaining the ability to modulate Met receptor activity.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite materials by creating covalently linked dimers of HGF variants. These dimers consist of two HGF variant molecules connected through disulfide bonds or other covalent linkages, forming a composite structure that exhibits enhanced binding affinity and stability compared to monomeric forms.

Inventive Principle:

Principle #40Composite materials

2Productivity

If recombinant expression is used to produce HGF variants, then protein supply is increased, but the expression yield is limited

Engineering Contradiction:

Improverecombinant expression yieldVSAvoidproduction efficiency

Core Design Contradiction:

ProductivityVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by optimizing expression conditions and protein engineering to improve recombinant production. Amino acid sequence modifications are designed to enhance protein stability and solubility, which directly improves expression yields in recombinant systems while facilitating scalable manufacturing.

Inventive Principle:

Principle #35Parameter changes

3Stability of the object's composition

If conventional protein formulations are used, then therapeutic delivery is enabled, but protein stability is limited

Engineering Contradiction:

Improveprotein stabilityVSAvoidtherapeutic consistency

Core Design Contradiction:

Stability of the object's compositionVSReliability

Solution Approach 1:

The patent employs composite materials by designing covalently linked dimeric structures of HGF variants. The covalent linkages between monomers provide structural stability and resistance to proteolytic degradation, while the overall dimeric architecture maintains the biological activity required for Met receptor modulation, ensuring therapeutic consistency.

Inventive Principle:

Principle #40Composite materials

4Reliability

If Met receptor antagonists are developed, then cancer therapy is enhanced, but the device complexity increases

Engineering Contradiction:

Improvecancer therapy efficacyVSAvoidmolecular structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies segmentation by dividing the HGF molecule into distinct functional domains and creating truncated variants that retain Met receptor binding capability while reducing overall molecular complexity. The N-terminal domain and Kringle domains are strategically utilized to create simplified yet effective antagonist structures.

Inventive Principle:

Principle #1Segmentation

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 HGF variants effectively modulate Met receptor activity, offering potent therapeutic options for cancer treatment and tissue repair while providing high-affinity binding and stability for in vivo and in vitro imaging.

Implementation Method 1

Methodology Applied

Scientific EffectMolecular binding:

Implementation Method 2

Development of polypeptide variants of Hepatocyte Growth Factor (HGF) that form covalently linked dimers with improved Met receptor binding affinity and stability

Methodology Applied

Scientific EffectCovalent bonding: Chemical Bonding

Data Source

PatentUS9556248B2Hepatocyte growth factor fragments that function as potent met receptor agonists and antagonists

Publication Date: 2017.01.31 THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV

AI summary

The NK1 fragment of hepatocyte growth factor (HGF) binds to and activates the Met receptor, a transmembrane receptor tyrosine kinase that plays a critical role in embryonic development and organ formation. The instant application discloses NK1 variant polypeptides which act as agonists or antagonists of HGF. Further disclosed are covalently linked NK1 variant polypeptides. Many of the disclosed variant polypeptides possess improved stability characteristics.