Alpha(v)beta(6) Integrin-Binding Peptides for Tumor Selectivity

Solution Overview

Problem

There is a need for tumor targeting agents that provide high tumor selectivity and specificity for αvβ6-expressing tumors, as existing agents like radiolabeled peptides have shown rapid metabolism and low binding affinity.

Innovation Solution

Development of peptides with specific amino acid sequences, such as VGDLTYLKQKVART, that selectively bind to αvβ6 integrin with enhanced binding affinity, potentially combined with moieties like PEG for improved stability and targeting, and used in conjugates with imaging or therapeutic agents.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If radiolabeled peptides are used for tumor targeting, then imaging capability is provided, but rapid metabolism and low binding affinity result in poor tumor selectivity and stability

Engineering Contradiction:

Improvetumor selectivityVSAvoidpeptide stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent modifies peptide parameters by incorporating non-natural amino acids with enhanced metabolic stability and optimized binding affinity. Specific amino acid substitutions (e.g., replacing metabolically labile residues with stable analogs) and sequence optimizations achieve at least 5-fold greater binding affinity for αvβ6 integrin while resisting enzymatic degradation, directly resolving the contradiction between reliability and stability.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite peptide structures by combining multiple functional elements: high-affinity binding motifs for αvβ6 integrin, metabolically stable non-natural amino acids, and conjugation sites for imaging or therapeutic agents. This composite approach enables simultaneous achievement of tumor selectivity, metabolic stability, and therapeutic/imaging functionality.

Inventive Principle:

Principle #40Composite materials

2Reliability

If peptide binding affinity to αvβ6 integrin is increased, then tumor targeting specificity is improved, but cross-reactivity with αvβ3 or αvβ8 integrins may increase

Engineering Contradiction:

Improvetargeting specificityVSAvoidcross-reactivity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing peptide sequences with specific local structural features that recognize unique epitopes on αvβ6 integrin. By optimizing local amino acid interactions at the binding interface (e.g., specific side-chain configurations, hydrogen bonding patterns, or hydrophobic contacts), the peptides achieve high specificity for αvβ6 while avoiding cross-reactivity with αvβ3 or αvβ8, even at enhanced binding affinities.

Inventive Principle:

Principle #3Local quality

3Stability of the object's composition

If peptides are modified with moieties like PEG for improved stability, then metabolic stability is enhanced, but molecular weight and potential immunogenicity increase

Engineering Contradiction:

Improvemetabolic stabilityVSAvoidmolecular complexity

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent modifies peptide parameters by incorporating non-natural amino acids with enhanced metabolic stability and optimized binding affinity. Specific amino acid substitutions (e.g., replacing metabolically labile residues with stable analogs) and sequence optimizations achieve at least 5-fold greater binding affinity for αvβ6 integrin while resisting enzymatic degradation, directly resolving the contradiction between reliability and stability.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11591369B2Alpha(v)beta(6) integrin-binding peptides and methods of use thereof

Publication Date: 2023.02.28 RGT UNIV OF CALIFORNIA

AI summary

The present invention provides peptides and peptide-conjugates that bind to αvβ6 integrin. The peptide-conjugates can be used for a variety of imaging and therapeutic applications. Methods of use and peptide optimization are also provided herein.