Engineered NY-ESO-1 TCR Constructs for Stable Anti-Tumor T Cells

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Solution Overview

Problem

Existing TCR-T therapies for cancer, particularly targeting NY-ESO-1, face challenges such as impaired efficacy, safety issues, and insufficient persistence of engineered T cells, leading to inadequate therapeutic outcomes and adverse effects.

Innovation Solution

Development of engineered T cell receptors (TCRs) with specific binding to the NY-ESO-1 epitope, characterized by unique CDR sequences and interchain disulfide bonds, encoded by nucleic acid constructs, which provide enhanced expression and functional avidity, allowing for improved anti-tumor responses.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional TCR-T therapies are used to target NY-ESO-1, then anti-tumor activity is achieved, but efficacy is impaired and therapeutic outcomes are inadequate

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidanti-tumor activity

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent applies parameter changes by modifying the TCR structure through specific amino acid substitutions in the CDR regions (particularly CDR3α and CDR3β) and engineering disulfide bond positions to optimize binding affinity and functional avidity for the NY-ESO-1 epitope, thereby improving therapeutic efficacy while maintaining safety

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite TCR constructs by combining engineered α and β chains with specific structural features including stabilized disulfide bonds, optimized framework regions, and tailored CDR sequences to form a composite receptor complex with enhanced stability and function

Inventive Principle:

Principle #40Composite materials

2Duration of action of moving object

If TCR-T therapies are administered, then immune response is activated, but persistence of engineered T cells is insufficient

Engineering Contradiction:

Improvepersistence of engineered T cellsVSAvoidtherapeutic outcome

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

The patent implements beforehand cushioning by engineering the TCR structure with stabilized disulfide bonds and optimized constant regions that protect the receptor from degradation and maintain structural integrity, thereby extending the persistence and survival of engineered T cells in the patient's immune system

Inventive Principle:

Principle #11Beforehand cushioning (Prior cushioning)

Solution Approach 2:

The patent achieves continuity of useful action through TCR designs that maintain sustained antigen recognition and signaling capability over time, preventing exhaustion and ensuring continuous anti-tumor activity through optimized binding kinetics and reduced tonic signaling

Inventive Principle:

Principle #20Continuity of useful action

3Reliability

If TCR transduction is performed to enhance anti-tumor function, then specificity is improved, but mispairing of endogenous and transfected TCRs occurs causing self-reactivity

Engineering Contradiction:

Improvetumor antigen specificityVSAvoidself-reactivity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies taking out by removing or neutralizing the problematic endogenous TCR components that cause mispairing, and instead introducing carefully engineered TCR constructs with unique structural features that prevent inappropriate pairing while maintaining specific recognition of the NY-ESO-1 epitope

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent uses intermediary structures such as engineered disulfide bonds and optimized framework regions that act as mediators to ensure proper pairing of transfected TCR chains while preventing mispairing with endogenous chains, thereby eliminating self-reactivity

Inventive Principle:

Principle #24Intermediary (Mediator)

4Productivity

If TCR expression is increased to improve functional avidity, then anti-tumor response is enhanced, but exhausted effectors are generated causing impaired therapeutic outcome

Engineering Contradiction:

Improvefunctional avidityVSAvoidtherapeutic outcome

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies partial or excessive action by optimizing TCR expression levels and binding affinity to achieve sufficient but not excessive antigen engagement, preventing overstimulation and exhaustion while maintaining high functional avidity for effective anti-tumor responses

Inventive Principle:

Principle #16Partial or excessive action

Solution Approach 2:

The patent implements periodic action through TCR designs that enable controlled, rhythmic signaling patterns that prevent continuous overstimulation and exhaustion, allowing engineered T cells to maintain functionality and persistence through optimized signal transduction kinetics

Inventive Principle:

Principle #19Periodic action

Data Source

PatentUS20260053853A1Engineered t cell receptor constructs for cancer therapy

Publication Date: 2026.02.26 HADASIT MEDICAL RESEARCH SERVICES & DEVELOPMENT LTD

AI summary

The invention relates to engineered T cell receptors (TCRs) directed to cancer testis antigen New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1), useful in the treatment of cancer. In particular, provided are isolated TCR polypeptides, as well as corresponding nucleic acid molecules and cell compositions, characterized by improved properties that are particularly adapted to cancer immunotherapy.