Modified HVEM Proteins for Selective Ligand Binding

Solution Overview

Problem

Existing treatments for herpes virus entry mediator (HVEM) proteins are hindered by promiscuous binding to multiple ligands, leading to off-target effects and complications in treating conditions like B-cell lymphomas and autoimmune disorders.

Innovation Solution

Development of HVEM proteins with specific amino acid substitutions, such as G72A, G72D, G72R, T73A, T73D, V74D, T73A, V74E, A76D, T82D, Y83A, T84D, T84F, H86D, N88A, N88D, G89D, L90A, L90D, L90R, L94A, L94D, which reduce binding to non-target ligands, and the creation of Chimeric Antigen Receptors (CARs) incorporating these modified HVEM proteins for targeted therapeutic applications.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If wild-type HVEM protein is used for therapy, then broad ligand binding capability is achieved, but off-target effects occur due to promiscuous binding to multiple ligands

Engineering Contradiction:

Improveligand binding capabilityVSAvoidoff-target effects

Core Design Contradiction:

Adaptability or versatilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by introducing specific amino acid substitutions at particular positions within the HVEM protein structure (positions 72, 73, 74, 76, 82, 83, 84, 86, 88, 89, 90, 94) to selectively modify ligand binding properties. These localized changes alter the binding interface characteristics to achieve selective binding to desired ligands while preventing binding to non-target ligands, thereby resolving the contradiction between broad adaptability and harmful off-target effects.

Inventive Principle:

Principle #3Local quality

2Adaptability or versatility

If HVEM protein binds to multiple ligands, then diverse signaling functions are activated, but therapeutic specificity is reduced

Engineering Contradiction:

Improvesignal transduction capabilityVSAvoidtherapeutic specificity

Core Design Contradiction:

Adaptability or versatilityVSManufacturing precision

Solution Approach 1:

The patent employs parameter changes by systematically modifying amino acid residues at specific positions in the HVEM protein sequence. These parameter changes (substitutions of charged, polar, or hydrophobic amino acids) alter the binding affinity parameters for different ligands, enabling the protein to maintain signaling functionality while achieving therapeutic specificity through controlled changes in binding characteristics.

Inventive Principle:

Principle #35Parameter changes

3Productivity

If wild-type HVEM is used in CAR therapy, then broad immune activation occurs, but treatment precision is compromised

Engineering Contradiction:

Improveimmune activation efficiencyVSAvoidtargeting accuracy

Core Design Contradiction:

ProductivityVSMeasurement precision

Solution Approach 1:

The patent applies local quality by introducing specific amino acid substitutions at particular positions within the HVEM protein structure (positions 72, 73, 74, 76, 82, 83, 84, 86, 88, 89, 90, 94) to selectively modify ligand binding properties. These localized changes alter the binding interface characteristics to achieve selective binding to desired ligands while preventing binding to non-target ligands, thereby resolving the contradiction between broad adaptability and harmful off-target effects.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS20250326817A1Herpes virus entry mediator proteins and methods of use thereof

Publication Date: 2025.10.23 KRONENBERG MITCHELL

AI summary

Provided herein, inter alia, are compositions including herpes virus entry mediator (HVEM) proteins and fragments thereof. The HVEM proteins provided herein may have modulated binding affinity to ligands and/or receptors compared to wild type HVEM proteins. The HVEM proteins provided herein are contemplated to be effective for treating diseases, particularly cancer and inflammatory diseases.