Universal T Cells via ERAD Hijacking for Allogeneic Compatibility

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Solution Overview

Problem

Current immunological therapies face challenges in generating universal T cells that are compatible for allogeneic administration, as they often trigger graft-versus-host disease (GVHD) and immune rejection due to T cell receptor (TCR) and human leukocyte antigen (HLA) mismatch.

Innovation Solution

The development of a hybrid multi-domain construct that disrupts TCR and HLA expression by hijacking the endoplasmic reticulum-associated degradation (ERAD) machinery, using viral ER-resident glycoproteins such as US2, US3, US11, and E19, to generate highly compatible autologous universal T cells for further genetic engineering.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If T cells are used for immunological therapy, then therapeutic efficacy is improved, but graft-versus-host disease and immune rejection occur due to TCR and HLA mismatch

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidGVHD and immune rejection

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts and removes the problematic TCR and HLA components from T cells through genetic disruption. By disabling TCR expression and modifying HLA class I molecules, the invention eliminates the sources of GVHD and rejection while preserving the therapeutic functionality of T cells for cancer immunotherapy

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent introduces universal T cells as an intermediary solution that bridges donor and recipient incompatibility. These engineered T cells with disrupted TCR and modified HLA serve as a universal donor product that can be administered to multiple recipients without triggering rejection or GVHD, mediating between donor T cell availability and recipient compatibility requirements

Inventive Principle:

Principle #24Intermediary (Mediator)

2Adaptability or versatility

If TCR and HLA expression are disrupted to generate universal T cells, then compatibility for allogeneic administration is improved, but T cell function may be compromised

Engineering Contradiction:

Improvecompatibility for allogeneic administrationVSAvoidT cell function

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent segments the T cell into functional and compatibility components. By selectively disrupting only TCR and HLA class I expression while preserving other T cell molecules and functions, the invention separates the compatibility issue from the therapeutic function, allowing universal T cells to maintain anti-tumor activity without causing GVHD or rejection

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent changes the molecular parameters of T cells by genetically disrupting TCR and HLA class I expression. This parameter modification transforms standard T cells into universal T cells with altered compatibility characteristics, enabling allogeneic administration while maintaining therapeutic function through preserved T cell activation and cytotoxic pathways

Inventive Principle:

Principle #35Parameter changes

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

This approach effectively suppresses TCR and HLA expression, reducing the risk of GVHD and immune rejection, thereby enhancing the compatibility and persistence of allogeneic T cells post-infusion, and allowing for further genetic engineering for therapeutic applications.

Implementation Method 1

The development of a hybrid multi-domain construct that disrupts TCR and HLA expression by hijacking the endoplasmic reticulum-associated degradation (ERAD) machinery

Methodology Applied

Scientific EffectEndoplasmic reticulum-associated degradation (ERAD):

Data Source

PatentUS12312407B2Universal T cells and the method of use thereof

Publication Date: 2025.05.27 YIZUN BIOPHARM SHANGHAI CO LTD

AI summary

A series of recombinant DNA constructs and a method is disclosed for use in immunological therapy in general; and in disrupting T cell receptor (TCR), human leukocyte antigens (HLA) class I and NKG2D (Natural-Killer Group 2, member D) ligand expression in particular, with the effect of producing highly compatible autologous universal T cells for further genetically engineering for allogeneic administration. A Universal T (UT) construct is provided and used, comprising a TCR antibody fragment fused to a transmembrane domain (TMD) and ER retention domain of adenovirus early region 3 glycoprotein E3-19k (E3/19K) (TCR-E3/19K RD). The Universal T (UT) construct can hijack ERAD machinery to arrest TCR and HLA molecules in endoplasmic reticulum (ER) and facilitate their translocation into the cytoplasm for ubiquitination and degradation by proteasomes.