Codon-Optimized Chimeric TCR for Enhanced Immune Cell Targeting

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Solution Overview

Problem

Existing immunotherapies for cancer, such as monoclonal antibodies and chimeric antigen receptors (CAR) T-cell therapies, lack the specificity and efficacy needed to effectively target and eliminate tumor cells, particularly in solid and blood-based malignancies.

Innovation Solution

Development of chimeric T cell receptors (TCRs) comprising a CAR scaffold with a CD28 costimulatory signaling region and a CD3ζ activation domain, codon-optimized for improved expression in immune cells, coupled with an antigen binding domain like scFv, to enhance targeted immune cell therapy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing immunotherapies such as monoclonal antibodies and CAR T-cell therapies are used, then treatment options for cancer are provided, but they lack the specificity and efficacy needed to effectively target and eliminate tumor cells

Engineering Contradiction:

Improvespecificity and efficacy in targeting tumor cellsVSAvoidability to target various cancer types

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent creates a universal chimeric TCR platform that can target multiple different cancer types by combining a standardized CAR scaffold with various antigen-binding domains. The modular design allows the same basic structure to be adapted for different cancer indications, achieving both high specificity through antigen-specific binding and broad versatility across solid and blood-based malignancies

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The invention combines elements from different immunotherapeutic approaches into a composite chimeric TCR molecule. It merges the antigen-specific binding capability of monoclonal antibodies (via scFv domains) with the cellular activation and costimulation mechanisms of CAR T-cell therapies (via CD3ζ and CD28 domains), creating a hybrid receptor that leverages the strengths of both approaches to achieve superior specificity and efficacy

Inventive Principle:

Principle #40Composite materials

2Reliability

If CAR scaffold with CD28 costimulatory signaling region and CD3ζ activation domain is used, then immune cell activation and targeting capability are enhanced, but the complexity of the receptor structure increases

Engineering Contradiction:

Improveimmune cell activation and targeting capabilityVSAvoidreceptor structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent merges multiple functional domains into a single chimeric TCR molecule: the antigen-binding scFv domain, the CD28 costimulatory signaling region with ectodomain/transmembrane/cytoplasmic domains, and the CD3ζ activation domain with ITAMs. This consolidation integrates antibody-type specificity with T-cell activation and costimulation functions into one unified receptor structure, enhancing capability while managing complexity through functional integration

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The chimeric TCR is designed as a segmented modular structure with distinct functional regions: the N-terminal antigen-binding domain, the middle CD28 costimulatory region with its three subdomains (ectodomain, transmembrane, cytoplasmic), and the C-terminal CD3ζ activation domain. This segmentation allows each component to perform its specialized function while maintaining overall structural organization and facilitating targeted optimization of individual modules

Inventive Principle:

Principle #1Segmentation

3Productivity

If codon optimization is applied for improved expression in immune cells, then expression levels and function are enhanced, but the manufacturing process becomes more complex

Engineering Contradiction:

Improveexpression levels and function in immune cellsVSAvoidmanufacturing process complexity

Core Design Contradiction:

ProductivityVSEase of manufacture

Solution Approach 1:

The patent applies codon optimization to change the nucleotide sequence parameters of the chimeric TCR gene without altering the amino acid sequence. By optimizing codon usage to match the preferences of immune cell translation machinery, the invention enhances expression levels and functional output. This parameter change at the nucleotide level achieves improved productivity while maintaining the same protein structure and function

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20250206800A1Chimeric T Cell Receptors, Nucleic Acids, And Methods Of Making And Using The Same

Publication Date: 2025.06.26 NANTBIOSCIENCE INC

AI summary

Compositions and methods for eradicating tumor cells using novel compositions are contemplated. In one aspect, a pharmaceutical composition comprising a CAR scaffold and an antigen binding domain in a single chimeric species is provided. In some aspects, the CAR scaffold may comprise a CD28 costimulatory signaling region and a CD3ζ (activation domain or a complete CD3ζ activation domain. In some aspects, the CAR scaffold may be codon-optimized for improved expression in mammalian cell lines and/or for improved function upon transfection into natural killer (NK) or other immune cells. In further aspects, the antigen binding domain may comprise a VL and VH domain linked by a spacer and may be codon optimized. A CD64 leader sequence may be attached to the antigen binding domain, e.g., at the N-terminus of the antigen binding domain.