CAR-T Cells with Intermediate Affinity for CD6 and CD19

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Solution Overview

Problem

Current chimeric antigen receptor (CAR) therapies for cancer and autoimmune diseases face challenges in targeting specific antigens effectively and often result in severe side effects due to over-activation of immune cells, leading to issues like cytokine release syndrome and immune exhaustion.

Innovation Solution

Development of CARs targeted to CD6, CD19, and IL-13Rα2, expressed in regulatory T cells (Tregs) with intermediate or low affinity, incorporating a CD152 (CTLA-4) cytoplasmic domain and a CD3 zeta signaling domain, to promote immunomodulatory activity and reduce adverse effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If high affinity CAR targeting is used, then antigen binding efficiency is improved, but immune cell over-activation and cytokine release syndrome occur

Engineering Contradiction:

Improveantigen binding efficiencyVSAvoidcytokine release syndrome

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by engineering CARs with intermediate or low affinity for target antigens (CD6, CD19, IL-13Rα2) instead of high affinity binding. This modification of the binding affinity parameter reduces over-activation of immune cells and prevents cytokine release syndrome while maintaining sufficient target recognition and therapeutic efficacy.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If strong CAR activation signaling is used, then tumor cell killing is improved, but immune cell exhaustion occurs

Engineering Contradiction:

Improvetumor cell killingVSAvoidimmune cell persistence

Core Design Contradiction:

ProductivityVSDuration of action of moving object

Solution Approach 1:

The patent modifies the activation signaling parameter by using intermediate or low affinity CAR designs that provide sustained, moderate signaling rather than strong transient signals. This prevents immune cell exhaustion and maintains T cell functionality and persistence over extended periods, thereby improving both tumor cell killing and duration of action.

Inventive Principle:

Principle #35Parameter changes

3Speed

If traditional CAR approach in effector T cells is used, then rapid anti-tumor response is achieved, but severe side effects and immune exhaustion occur

Engineering Contradiction:

Improveanti-tumor response speedVSAvoidadverse cytokine release

Core Design Contradiction:

SpeedVSObject-affected harmful factors

Solution Approach 1:

The patent changes the key parameter of CAR affinity from high to intermediate or low, which modulates the activation threshold and signaling intensity. This results in a more controlled and sustained anti-tumor response that maintains effectiveness while significantly reducing adverse cytokine release and immune-related side effects.

Inventive Principle:

Principle #35Parameter changes

4Measurement precision

If high affinity antigen binding is used, then target recognition is improved, but cell lifespan is reduced due to over-activation

Engineering Contradiction:

Improvetarget recognitionVSAvoidCAR-T cell lifespan

Core Design Contradiction:

Measurement precisionVSDuration of action of stationary object

Solution Approach 1:

The patent optimizes the binding affinity parameter to intermediate or low levels, which allows sufficient target recognition and binding while avoiding the over-activation that leads to reduced cell lifespan. This parameter adjustment extends CAR-T cell persistence and functionality in vivo.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20230076643A1Methods of making and using regulatory t cells and effector t cells having chimeric antigen receptors targeted to CD6, CD19, and/or an il-13r for treatment of autoimmune disorders and cancers

Publication Date: 2023.03.09 CITY OF HOPE

AI summary

Provided herein are, inter alia, CAR-T cell compositions targeting CD6, CD19, and/or an IL-13R, and methods useful for treating autoimmune diseases and cancer.