CD6 CAR-Treg Composition for Safer Type 1 Diabetes Immunotherapy
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Solution Overview
Problem
Current therapeutic strategies for Type 1 diabetes mellitus (TID) are limited in effectively targeting pancreatic islet-infiltrating lymphocytes while protecting and replenishing functional beta cell mass, leading to autoimmune destruction and low proliferative and regenerative potential of beta cells.
Innovation Solution
Development of chimeric antigen receptors (CARs) targeted to the CD6 molecule, expressed in regulatory T cells (Tregs), to inhibit pro-inflammatory T-cells and enhance beta cell survival and function, using low-affinity CD6 CARs in a CD6low/â subset of Tregs to avoid over-activation and extend cell lifespan.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CARs with high affinity for CD6 are used, then the ability to target and inhibit pro-inflammatory T-cells is improved, but the risk of over-activation and adverse cytokine release syndrome increases
Solution Approach 1:
The patent applies parameter changes by modifying the affinity of the CAR-CD6 interaction. Specifically, it uses low-affinity CD6 CARs (with KD values ranging from 10^-7 to 10^-9 M) instead of high-affinity CARs. This parameter modification allows the CARs to maintain sufficient targeting efficiency while reducing over-activation and cytokine release syndrome, thereby resolving the contradiction between reliability and harmful effects.
2Productivity
If CARs are expressed in T effector cells, then the ability to directly attack and eliminate pro-inflammatory T-cells is improved, but the risk of triggering adverse cytokine release syndrome and ensuring safety is worsened
Solution Approach 1:
The patent applies the inversion principle by reversing the conventional approach. Instead of using T effector cells to attack pro-inflammatory T-cells (which causes cytokine release syndrome), it inverts the strategy by using T regulatory cells (Tregs) that naturally suppress inflammation. The Tregs express low-affinity CD6 CARs to selectively inhibit pro-inflammatory T-cells while maintaining safety, thus resolving the contradiction between productivity and harmful effects.
3Reliability
If high-affinity CD6 CARs are used in Tregs, then the inhibitory signaling strength is improved, but the lifespan of adoptively transferred cells is reduced due to over-activation
Solution Approach 1:
The patent applies parameter changes by optimizing the affinity parameter of the CAR-CD6 interaction. It employs low-affinity CARs with specific KD values (10^-7 to 10^-9 M) that provide sufficient inhibitory signaling while avoiding over-activation. This parameter optimization extends the lifespan of adoptively transferred Treg cells, resolving the contradiction between reliability and duration of action.
4Productivity
If therapeutic strategies target beta-cell antigens, then the ability to eliminate pro-inflammatory T-cells is improved, but the damage to pancreatic islets and loss of functional beta cell mass increases
Solution Approach 1:
The patent applies the intermediary principle by introducing CD6 as an intermediary target. Instead of directly targeting beta-cell antigens (which causes islet damage), it uses CD6 as an intermediary marker on pro-inflammatory T-cells. The low-affinity CD6 CARs in Tregs selectively interact with CD6 on pathogenic T-cells, providing a safe intermediary approach that eliminates harmful immune cells without damaging pancreatic islets, thus resolving the contradiction between productivity and harmful effects.
Data Source
AI summary
Provided herein are, inter alia, CD6 targeting CAR-T cell compositions and methods useful for treating autoimmune diseases (e.g., Type I diabetes).