CD8αβ Co-Receptor Expression Reprograms CD4 T Cells for Cytotoxicity

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Existing TCR-transgenic T cell therapies face limitations due to low functional avidity and potential off-target effects, and CD8+ T cells have impaired activation due to limited endogenous CD8 co-receptor availability, while CD4+ T cells lack cytotoxic function despite crucial helper roles in immune responses.

Innovation Solution

Forced expression of the CD8αβ co-receptor in both CD4+ and CD8+ T cells, combined with engineered antigen receptors, enhances TCR function and reprograms CD4+ T cells into hybrid cytotoxic and helper cells, improving anti-tumor activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If high affinity TCRs are isolated from allogeneic repertoires or synthetic TCRs are generated, then T cell recognition of tumor associated antigens is improved, but severe cross-reactivity and off-target effects occur

Engineering Contradiction:

ImproveT cell recognition of tumor associated antigensVSAvoidcross-reactivity and off-target effects

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

The patent changes the functional parameters of T cells by forcing expression of CD8αβ co-receptor in CD4+ T cells and optimizing CD8 expression in CD8+ T cells. This parameter change enables low affinity TCRs to achieve high functional avidity through enhanced TCR signaling, avoiding the need for high affinity TCRs that cause off-target effects

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

Instead of trying to increase TCR affinity to improve tumor recognition, the patent inverts the approach by enhancing co-receptor expression to amplify the signaling of existing low affinity TCRs. This reverse strategy achieves effective tumor recognition without the harmful cross-reactivity associated with high affinity TCRs

Inventive Principle:

Principle #13The other way round (Inversion)

2Productivity

If CD8+ T cells are engineered with viral vectors to express transgenic TCRs, then T cell expansion is improved, but functional activation is impaired due to limited endogenous CD8 co-receptor availability

Engineering Contradiction:

ImproveT cell expansionVSAvoidfunctional activation

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent changes the expression level parameter of the CD8 co-receptor by forcing its expression in CD4+ T cells and enhancing it in CD8+ T cells. This creates a balanced copy number ratio between TCR and CD8, enabling full and sustained functional activation while maintaining the expanded T cell population

Inventive Principle:

Principle #35Parameter changes

3Adaptability or versatility

If CD4+ T cells are used for adoptive transfer, then helper functions are provided, but cytotoxic function is lacking

Engineering Contradiction:

Improvehelper functionsVSAvoidcytotoxic function

Core Design Contradiction:

Adaptability or versatilityVSProductivity

Solution Approach 1:

The patent makes CD4+ T cells universal by forcing expression of CD8αβ co-receptor, enabling them to perform both helper functions (intrinsic to CD4+ cells) and cytotoxic functions (typically associated with CD8+ cells). This multi-functional CD4+ T cell can recognize and kill tumor cells directly while also providing helper support to other immune cells

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20250269032A1REPROGRAMMING CD4 T CELLS INTO CYTOTOXIC CD8 CELLS BY FORCED EXPRESSION OF CD8aB AND CLASS 1 RESTRICTED T CELL RECEPTORS

Publication Date: 2025.08.28 BAYLOR COLLEGE OF MEDICINE

AI summary

Embodiments of the disclosure include methods and compositions related to improvements of T cell therapy. In particular embodiments, CD8+ T cell therapy is enhanced upon expression of transgenic E08αβ co-receptor in the CD8+ T cells. In certain embodiments, CD4+ T cells are rendered to have cytotoxic cell function for adoptive transfer upon expression of transgenic E08αβ co-receptor in the CD4+ T cells. In specific embodiments, TCR-expressing and E08αβ co-receptor-expressing CD4+ and CD8+ T cells are utilized in adoptive transfer.