D7 scFv CAR T Cells for PSMA-Positive Prostate Cancer
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Solution Overview
Problem
Current treatments for advanced prostate cancer are limited, and existing chimeric antigen receptors (CARs) targeting prostate-specific membrane antigen (PSMA) have shown low potency in eliminating tumor cells due to the tumor microenvironment's restrictive effects on T cell activity.
Innovation Solution
Development of chimeric antigen receptors (CARs) for immune cells, specifically T cells, that incorporate an antigen-binding fragment derived from the D7 scFv, combined with co-stimulatory domains like CD28 or 4-1BB, to enhance antigen-specific activation and cytotoxicity against PSMA-expressing tumor cells, while minimizing immunogenicity through humanization and optimized genetic delivery methods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing chimeric antigen receptors (CARs) are used to target PSMA, then tumor cell elimination is achieved, but the potency is low due to tumor microenvironment restrictions on T cell activity
Solution Approach 1:
The patent creates composite chimeric antigen receptors by combining the D7 scFv antigen-binding domain with co-stimulatory domains (CD28, 4-1BB) and signaling domains (CD3ζ). This composite structure integrates multiple functional elements to overcome tumor microenvironment suppression and enhance T cell potency against PSMA-positive tumors
Solution Approach 2:
The patent modifies key parameters of the CAR structure by using the D7 scFv domain with optimized amino acid sequence (SEQ ID NO:1) and combining it with specific co-stimulatory domains. These parameter changes in the CAR molecular structure result in significantly enhanced in vitro cytotoxicity and in vivo antitumor activity compared to existing CARs
2Object-affected harmful factors
If humanization and optimized genetic delivery methods are used, then immunogenicity is minimized, but the complexity of the development process increases
Solution Approach 1:
The patent uses humanized versions of the D7 scFv domain that replicate the antigen-binding functionality while reducing immunogenicity. The humanized sequences (e.g., SEQ ID NOs: 15-23) are copied and optimized for expression in human T cells, maintaining therapeutic efficacy while minimizing immune rejection
Solution Approach 2:
The CAR construct is segmented into distinct functional domains: the D7 scFv antigen-binding domain, hinge region, transmembrane domain, co-stimulatory domains (CD28, 4-1BB), and signaling domain (CD3ζ). This segmentation allows independent optimization of each domain for reduced immunogenicity while maintaining overall functionality
3Quantity of substance
If a low effector-to-target ratio is used, then fewer CAR-expressing immune cells are needed, but the challenge of achieving sufficient tumor elimination with limited cells increases
Solution Approach 1:
The patent creates dynamically active CAR-expressing T cells that can rapidly expand and persist in the tumor microenvironment. The co-stimulatory domains enable sustained T cell activation and proliferation, allowing a small initial number of infused cells to expand into a large population capable of complete tumor elimination
Solution Approach 2:
The CAR-expressing T cells are pre-engineered ex vivo with optimized D7-based CAR constructs before infusion. This preliminary genetic modification ensures that the cells are pre-equipped with enhanced cytotoxicity and persistence capabilities, enabling them to effectively eliminate tumors even at low effector-to-target ratios
Data Source
AI summary
The present invention relates to a novel chimeric antigen receptor (CAR) comprising an antigen-binding fragment which binds specifically to PSMA antigen, and a method of manufacturing high-quality CAR T cell products by transfection and/or transduction of T cells therewith, which allows to eradicate tumors in vivo alone or in combination with pharmaceutical drugs, such chemotherapies, biopharmaceutical drugs, such as antibodies, or small-molecule drugs, such as protein kinase inhibitors.