Truncated EGFR Marker for Genetically Modified Cell Selection

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Solution Overview

Problem

Current methods for treating HIV infection, such as antiretroviral drug therapy (ART), are costly and have significant side effects, and CAR T cell therapy is challenging to administer effectively due to the need for target antigens which are minimal during ART, and there are difficulties in manufacturing and selecting genetically modified therapeutic cells.

Innovation Solution

A nucleic acid construct comprising a polynucleotide encoding a gene editing agent, a linker peptide, and a truncated epidermal growth factor receptor (tEGFR) is used to identify and enrich genetically modified cells by expressing tEGFR, allowing for their selection and use in therapeutic applications.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CAR T cell therapy is administered to treat HIV, then therapeutic efficacy is improved, but the therapy fails to persist because HIV-1 antigenemia is minimal during ART

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidCAR T cell persistence

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent changes the target parameter from HIV-1 antigens (which are minimal during ART) to endogenous cell surface proteins (CD3, CD4, CD8, or CD28) that are consistently expressed. This parameter change ensures CAR T cells can persist and function throughout the patient's body without relying on fluctuating viral antigen levels.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

Instead of targeting the virus directly (HIV-1 antigens), the invention inverts the approach by targeting host cell proteins that are naturally present on all nucleated cells. This inversion allows CAR T cells to track and kill infected cells through antigen presentation rather than direct viral antigen recognition.

Inventive Principle:

Principle #13The other way round (Inversion)

2Reliability

If genetically modified therapeutic cells are manufactured, then therapeutic capability is improved, but manufacturing scalability and selection efficiency deteriorate

Engineering Contradiction:

Improvetherapeutic capabilityVSAvoidmanufacturing scalability

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent employs selectable markers (antibiotic resistance genes, fluorescent proteins, or enzymatic markers) that allow genetically modified cells to self-identify and self-select during manufacturing. This self-service mechanism enables automated flow cytometry-based sorting and simplifies the manufacturing process, significantly improving scalability and selection efficiency.

Inventive Principle:

Principle #25Self-service

3Measurement precision

If selection markers are used to identify genetically modified cells, then selection precision is improved, but manufacturing complexity increases

Engineering Contradiction:

Improveselection precisionVSAvoidmanufacturing complexity

Core Design Contradiction:

Measurement precisionVSDevice complexity

Solution Approach 1:

The patent replaces complex manual selection methods with flow cytometry-based automated sorting. By using fluorescent or enzymatic markers that can be detected optically, the system substitutes mechanical/manual cell-by-cell inspection with high-speed optical detection and magnetic-actuated sorting, dramatically improving precision while reducing operational complexity.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Data Source

PatentUS20230167431A1Tagged gene editing technology for clinical cell sorting and enrichment

Publication Date: 2023.06.01 CITY OF HOPE

AI summary

Provided herein, inter alia, are constructs and methods for making genetically modified cells that express truncated EGFR (tEGFR). The constructs can be used for identifying, selecting and determining efficacy of the genetically modified cells. Further provided are methods of using the genetically modified cells for treating diseases.