CD2-Deficient CAR Tregs Conversion Resistance
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Solution Overview
Problem
Current CAR Treg cell therapies for transplantation and autoimmunity face challenges due to plasticity and inefficient trafficking, leading to potential organ rejection, as they can convert to effector T cells and be affected by T cell-depleting conditioning regimens, necessitating the development of conversion-resistant and condition-resistant CAR Tregs.
Innovation Solution
Engineering CAR Tregs to be deficient in cell-surface markers like CD2 using CRISPR technology, which not only makes them resistant to conversion and conditioning regimens but also enhances their functionality, achieved through a one-step method involving the removal or inhibition of the CD2 molecule.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR Tregs are used for immunosuppression, then immune tolerance is promoted, but they can convert to effector T cells and cause organ rejection
Solution Approach 1:
The patent removes the CD2 molecule from the CAR Treg cell surface through CRISPR/Cas9-mediated gene editing. By extracting this specific molecule that enables conversion to effector T cells, the Treg phenotype stability is enhanced while preventing harmful conversion events.
Solution Approach 2:
The patent modifies the cellular parameter of CD2 expression by completely eliminating it through genetic deletion. This parameter change transforms the Treg cells into a CD2-negative state that resists conversion to effector T cells while maintaining immunosuppressive function.
2Productivity
If T cell-depleting conditioning regimens are used to prepare for CAR Treg therapy, then space is created for CAR Treg engraftment, but CAR Tregs are depleted along with other T cells
Solution Approach 1:
The patent creates a local quality difference by making CAR Tregs CD2-negative while leaving other T cells intact. This selective modification allows the conditioning regimen to deplete CD2-positive endogenous T cells while sparing the engineered CD2-negative CAR Tregs, enabling their preferential engraftment.
Solution Approach 2:
Instead of making CAR Tregs resistant to conditioning through overexpression of protective molecules, the patent inverts the approach by completely removing the CD2 target that conditioning regimens attack. This inversion makes CAR Tregs invisible to anti-CD2 conditioning while other T cells remain vulnerable.
3Reliability
If multiple engineering steps are used to create conversion-resistant CAR Tregs, then stability is improved, but manufacturing complexity increases
Solution Approach 1:
The patent achieves conversion resistance through a single extraction operation: removing the CD2 molecule via CRISPR/Cas9 gene editing. This single-step approach eliminates the need for multiple sequential engineering operations while achieving the desired conversion-resistant phenotype.
Solution Approach 2:
The single CRISPR/Cas9 gene editing step simultaneously achieves multiple objectives: it removes CD2 to prevent conversion to effector T cells, creates CD2-negative status for resistance to conditioning regimens, and enables preferential engraftment. This multi-functional approach simplifies the overall engineering process.
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
The CD2-deficient CAR Tregs demonstrate increased stability and immune suppression potency, effectively preventing conversion to effector T cells and resisting T cell-depleting conditioning, thereby improving safety and efficacy in transplantation and autoimmune disease treatment.
Implementation Method 1
A method utilizing CRISPR technology to remove a cell-surface marker, e.g., CD2 molecule, from CAR Tregs genome can be used to make CAR Tregs resistant to a T cell-depleting conditioning regimen involving an antibody
Data Source
AI summary
CAR Tregs and Tregs are provided which are both conversion-resistant and condition-resistant. The Treg cells are engineered such that they are deficient in or substantially devoid of a cell-surface marker or antigen.