Humanized Chimeric Notch Receptors for Low-Immunogenic Gene Control

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Solution Overview

Problem

The immunogenicity of chimeric Notch receptors, particularly those using GAL4-VP16 transcriptional machinery, limits their application in human gene therapy and immunotherapy for solid tumors due to host rejection, and the delivery of drugs or activation of immune cells in solid tumors is challenging, especially with HIV-1-based lentivirus vectors in macrophages.

Innovation Solution

Genetically engineer chimeric Notch receptors in monocyte/macrophage lineage cells using humanized transcription factors, such as HNF1 DNA binding domains with human transcriptional activator domains like p65 (RelA), reducing immunogenicity and enabling efficient gene expression.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If GAL4-VP16 transcriptional machinery is used in chimeric Notch constructs, then gene expression control is achieved, but immunogenicity increases leading to host rejection

Engineering Contradiction:

Improvegene expression controlVSAvoidimmunogenicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the biochemical parameters of the transcriptional machinery by replacing yeast-derived GAL4 DNA-binding domain with human HNF1 alpha DNA-binding domain, and replacing viral VP16 transactivation domain with human p65 transactivation domain. This parameter change in protein origin reduces immunogenicity while maintaining gene expression control functionality.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a humanized version of the transcriptional machinery that copies the functional architecture of GAL4-VP16 but uses human-derived protein sequences. The HNF1 alpha-p65 system replicates the DNA-binding and transactivation functions of GAL4-VP16 while being immunologically compatible with human hosts.

Inventive Principle:

Principle #26Copying

2Productivity

If HIV-1-based lentivirus vectors are used for genetic engineering of macrophages, then gene delivery is achieved, but infection is inhibited by SAMHD1 protein

Engineering Contradiction:

Improvegene delivery efficiencyVSAvoidinfection efficiency

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent introduces Vpx protein as an intermediary that mediates between the HIV-1 lentivirus vector and macrophage cells. Vpx acts as a molecular mediator that degrades SAMHD1 restriction factor, thereby enabling efficient viral entry and gene delivery into macrophages that would otherwise be resistant to HIV-1 infection.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Object-affected harmful factors

If chimeric Notch receptors with humanized transcription factors are used, then immunogenicity is reduced, but delivery to solid tumors becomes more challenging

Engineering Contradiction:

ImproveimmunogenicityVSAvoiddelivery to solid tumors

Core Design Contradiction:

Object-affected harmful factorsVSEase of manufacture

Solution Approach 1:

The patent employs preliminary action by using Vpx-pre-treated lentivirus vectors that have already overcome the SAMHD1 barrier before encountering the tumor microenvironment. This preliminary preparation ensures that the vectors are primed for efficient macrophage infection and gene delivery upon reaching solid tumors, addressing the delivery challenge while maintaining reduced immunogenicity.

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS12617825B2Methods and compositions for reducing the immunogenicity of chimeric notch receptors

Publication Date: 2026.05.05 CELL DESIGN LABS INC

AI summary

The present invention relates to methods and compositions for reducing the immunogenicity of chimeric Notch receptors, and specifically to transcription factors useful for controlling gene expression delivered to tissues by such chimeric Notch receptors.