CD28-Targeting CAR-T Cells With Disrupted Endogenous Gene
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Solution Overview
Problem
Current CAR-T cell therapies are ineffective for treating T-cell lineage malignancies due to the lack of specific target antigens and the challenge of fratricide, leading to severe immune deficiency and limited expansion of CAR-modified T cells, with no effective alternative treatments available besides allogeneic stem cell transplants that come with significant risks.
Innovation Solution
Development of modified T cells with a disrupted endogenous CD28-encoding gene and a chimeric antigen receptor (CAR) that specifically targets CD28, allowing for selective targeting of CD28-expressing T cells while minimizing fratricide and immune compromise, using gene editing techniques to introduce the CAR and disrupt CD28 expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells target antigens expressed on normal T cells (such as CD2, CD5, or CD7), then T-cell malignancies can be treated, but severe immune deficiency and T cell aplasia occur due to depletion of physiologic T cells
Solution Approach 1:
The patent applies local quality by disrupting the endogenous CD28 gene specifically in the CAR-T cells to create a localized functional difference. This allows the CAR-T cells to target CD28 on malignant T cells while normal T cells retain their CD28 function, thus achieving selective cytotoxicity without depleting the overall T cell population and avoiding severe immune deficiency
Solution Approach 2:
The patent converts the harmful effect of CD28 expression (which enables fratricide and limits expansion) into a benefit by disrupting the endogenous CD28 gene. This disruption prevents fratricide and enables robust expansion of CAR-T cells, while the CAR component continues to provide targeting capability against CD28-expressing malignant cells
2Reliability
If CAR-T cells express the targeted antigen (CD28), then targeting is achieved, but fratricide occurs and expansion of CAR-modified T cells is limited
Solution Approach 1:
The patent creates local quality differences by disrupting the endogenous CD28 gene specifically in CAR-T cells. This allows the CAR component to provide CD28 targeting capability while the disrupted endogenous gene prevents fratricide, enabling both specific targeting and robust expansion of CAR-modified T cells
Solution Approach 2:
The patent segments the CD28 function into two separate components: the CAR component that provides targeting capability and the endogenous CD28 gene that provides co-stimulatory function. By disrupting only the endogenous gene while preserving the CAR targeting function, the patent eliminates fratricide while maintaining targeting specificity and enabling expansion
3Object-affected harmful factors
If suitable target antigens are found that are exclusively expressed on malignant T cells, then selective targeting without immune deficiency is achieved, but no such antigens are currently known
Solution Approach 1:
Instead of searching for rare antigens that are exclusively expressed on malignant T cells, the patent inverts the approach by using a common antigen (CD28) that is widely expressed on T cells. The selectivity is achieved not through antigen rarity but through genetic disruption of the endogenous CD28 gene in CAR-T cells, making them resistant to fratricide while maintaining targeting capability
Data Source
AI summary
The present invention relates to a modified T cell, comprising (a) a disrupted endogenous CD28-encoding gene; and (b) a polynucleotide encoding a chimeric antigen receptor (CAR), wherein the CAR comprises in its ectodomain at least one antigen binding moiety that is capable of specific binding to the extracellular portion of CD28. The invention furthermore relates to a population of the modified T cells, to a method for generating modified T cells and medical and non-medical uses thereof.