Bispecific CAR-T Cells Targeting CD19 and CD20

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Solution Overview

Problem

Current CAR-T cell therapies targeting CD19 for treating B-cell malignancies face challenges with antigen escape, leading to relapse in patients, as tumor cells can down-regulate or lose CD19 expression, limiting treatment efficacy.

Innovation Solution

Development of a bispecific chimeric antigen receptor (CAR) that simultaneously targets CD19 and CD20, combining anti-CD20 and anti-CD19 single-chain variable fragments (scFv) with a hinge region, transmembrane domain, and intracellular signaling domains, to enhance tumor recognition and reduce immune escape.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If CD19-targeted CAR-T cell therapy is used, then initial response rate is high (90% complete remission), but relapse rate increases (11-40% relapse) due to antigen escape

Engineering Contradiction:

Improveinitial response rateVSAvoidrelapse rate

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The CAR-T cell receptor is designed to recognize multiple antigens (CD19 and CD20) simultaneously, making the therapy universally effective against B-cell malignancies regardless of which antigen is expressed. This multi-specificity prevents antigen escape by ensuring that loss or downregulation of one antigen does not confer escape, as the other antigen can still be targeted.

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Device complexity

If single-antigen CAR-T therapy is used, then treatment simplicity is maintained, but adaptability to antigen escape is poor

Engineering Contradiction:

Improvetherapy simplicityVSAvoidadaptability to antigen escape

Core Design Contradiction:

Device complexityVSAdaptability or versatility

Solution Approach 1:

Multiple antigen-specific binding domains (CD19 and CD20 scFv) are merged into a single CAR-T cell receptor structure. This combination allows the therapy to adapt to antigen escape by targeting alternative antigens, while maintaining relatively simple therapy administration compared to using multiple separate CAR-T cell products.

Inventive Principle:

Principle #5Merging (Combining)

3Reliability

If CD19-negative tumor cells escape, then treatment failure occurs, but expanding target to CD20 can treat CD19-negative patients

Engineering Contradiction:

Improvetreatment failure preventionVSAvoidtreatment expansion to CD19-negative patients

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The bispecific CAR-T cell can universally target both CD19 and CD20 antigens, enabling treatment of patients with CD19-negative B-cell malignancies through CD20 targeting. This expands the therapeutic indication beyond CD19-positive diseases while maintaining reliability by providing backup targeting capability.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20230104705A1Combined chimeric antigen receptor targeting CD19 and CD20 and application thereof

Publication Date: 2023.04.06 ABELZETA INC

AI summary

Provided is a combined chimeric antigen receptor targeting CD19 and CD20 and application thereof. Specifically, provided is a combined chimeric antigen receptor targeting CD19 and CD20, which comprises a scFv targeting CD19 and CD20, a hinge region, a transmembrane region, and an intracellular signaling domain. Provided is a nucleic acid molecule encoding the chimeric antigen receptor and a corresponding expression vector, a CAR-T cell, and applications thereof. The experimental results show that the chimeric antigen receptor shows extremely high killing ability against tumor cells. The chimeric antigen receptor targets CD19 and/or CD20 positive cells and can be used to treat CD19 and/or CD20 positive B-cell lymphoma, leukemia and other diseases.