CD19 CAR With 4g7 scFv Reduces T-Cell Exhaustion

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Solution Overview

Problem

Current CD19-specific chimeric antigen receptor (CAR) therapies for cancer treatment face challenges such as cytokine release syndrome, neurotoxicity, and T-cell exhaustion, which can limit their efficacy and durability of responses in patients with B-cell malignancies.

Innovation Solution

A new CD19-specific CAR with specific heavy and light chain variable region complementarity determining regions (CDRs) and an scFv orientation that reduces T-cell exhaustion and interferon-gamma release, incorporating a CD8 stalk spacer and a 41BB-Zeta intracellular signaling domain, is developed to enhance targeting efficiency and persistence.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If fmc63-based CARs are used for CD19 targeting, then T-cell activation and cancer cell killing efficacy are achieved, but cytokine release syndrome and neurotoxicity occur

Engineering Contradiction:

ImproveCAR therapy efficacyVSAvoidcytokine release syndrome and neurotoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the antigen-binding domain parameters by using a novel scFv derived from the 4g7 hybridoma instead of the traditional fmc63 scFv. This parameter change in the antibody specificity modifies the CAR's interaction with CD19, achieving reduced cytokine release and neurotoxicity while maintaining anti-leukaemic activity.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If conventional CAR designs are used, then initial cancer response is achieved, but T-cell exhaustion and loss of persistence occur

Engineering Contradiction:

Improveinitial cancer responseVSAvoidT-cell persistence

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent modifies the CAR structure by incorporating a CD28 costimulatory domain alongside the CD3-zeta signaling domain, creating a second-generation CAR design. This parameter change in the signaling domain architecture provides sustained T-cell activation and persistence while reducing exhaustion.

Inventive Principle:

Principle #35Parameter changes

3Productivity

If high-activity CARs are used to improve cancer killing, then efficacy increases, but interferon-gamma release and toxicity increase

Engineering Contradiction:

Improvecancer cell killing rateVSAvoidinterferon-gamma release

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent changes the antibody specificity parameter by using the 4g7 scFv which has different affinity and signaling characteristics compared to fmc63. This parameter change results in maintained cancer cell killing efficacy with reduced interferon-gamma release and associated toxicity.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20230220077A1Chimeric Antigen Receptor (CAR) Comprising A CD19-Binding Domain

Publication Date: 2023.07.13 AUTOLUS LIMIED

AI summary

There is provided a chimeric antigen receptor (CAR) comprising a CD19-binding domain which comprises a) a heavy chain variable region (VH) having complementarity determining regions (CDRs) with the following sequences: CDR1—GY-AFSSS (SEQ ID No. 1); CDR2—YPGDED (SEQ ID No. 2) CDR3—SLLYGDYLDY (SEQ ID No. 3); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1—SASSSVSYMH (SEQ ID No. 4); CDR2—DTSKLAS (SEQ ID No. 5) CDR3—QQWNINPLT (SEQ ID No. 6). There is also provided a cell comprising such a CAR, and the use of such a cell in the treatment of cancer, in particular a B cell malignancy.