CD19 CAR scFV 4G7 Epitope Selection for T Cell Proliferation

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Solution Overview

Problem

Current chimeric antigen receptors (CARs) for treating B-cell lymphomas and leukemia, such as those targeting CD19, face challenges in achieving prolonged T-cell proliferation and clinical efficacy due to limited compatibility and antigen-independent activation mechanisms.

Innovation Solution

Development of a CD19-specific chimeric antigen receptor (4G7-CAR) with a scFV derived from the CD19 monoclonal antibody 4G7, which confers a prolonged 'activated' state to T cells independently of antigen binding, enhancing cell proliferation and antigen-independent expansion.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional CARs targeting CD19 are used, then T-cell specificity toward B-cell malignancies is achieved, but prolonged T-cell proliferation and clinical efficacy are limited

Engineering Contradiction:

Improveclinical efficacyVSAvoidT-cell proliferation duration

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent modifies the CAR structure by changing the scFV specificity from FMC63 to 4G7, which binds to a different epitope on CD19. This parameter change in antibody specificity results in prolonged T-cell activation and extended proliferation duration, directly resolving the contradiction between clinical efficacy and proliferation duration.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The 4G7-CAR enables continuous T-cell activation and proliferation by maintaining a prolonged activated state independently of continuous antigen binding. This continuity of useful action allows T cells to sustain effector functions over extended periods, improving both clinical efficacy and proliferation duration simultaneously.

Inventive Principle:

Principle #20Continuity of useful action

2Productivity

If CARs are designed with standard scFV regions, then T-cell activation is achieved, but antigen-independent activation and prolonged expansion are limited

Engineering Contradiction:

ImproveT-cell expansionVSAvoidactivation mechanism dependency

Core Design Contradiction:

ProductivityVSEase of operation

Solution Approach 1:

The 4G7-CAR enables T cells to activate and expand independently of continuous external antigen stimulation. The CAR structure itself provides the activation signal, making the system self-sustaining and reducing dependency on external antigens for prolonged expansion, thus improving productivity while simplifying activation mechanism requirements.

Inventive Principle:

Principle #25Self-service

Data Source

PatentUS20240269178A1CD19 specific chimeric antigen receptor and uses thereof

Publication Date: 2024.08.15 CELLECTIS SA

AI summary

The present invention relates to chimeric antigen receptors (CAR). CARs are able to redirect immune cell specificity and reactivity toward a selected target exploiting the ligand-binding domain properties. In particular, the present invention relates to a Chimeric Antigen Recept—or in which extracellular ligand binding is a scFV derived from a CD19 monoclonal antibody, preferably 4G7. The present invention also relates to polynucleotides, vectors encoding said CAR and isolated cells expressing said CAR at their surface. The present invention also relates to methods for engineering immune cells expressing 4G7-CAR at their surface which confers a prolonged “activated” state on the transduced cell. The present invention is particularly useful for the treatment of B-cells lymphomas and leukemia.