High-Avidity WT1 T Cell Receptors for Tumor Cell Killing

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Solution Overview

Problem

Isolating T cells with high affinity TCRs specific for tumor antigens is difficult due to central tolerance mechanisms that eliminate such cells, limiting the effectiveness of adoptive T cell immunotherapy for diverse malignancies, particularly those expressing WT1 protein.

Innovation Solution

A high-throughput sequencing-based approach identifies TCRs with high functional avidity for the WT1 peptide:MHC complex, characterized by independent CD8 binding and low surface expression, enabling the synthesis and evaluation of 27 TCRs with enhanced antigen-specificity and affinity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If central tolerance mechanisms are used to eliminate self-reactive T cells, then autoimmune responses are prevented, but high affinity TCRs specific for tumor antigens are eliminated

Engineering Contradiction:

Improveprevention of autoimmune responsesVSAvoidavailability of high affinity TCRs

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent extracts high affinity TCRs from the peripheral blood of cancer patients using flow cytometry to isolate T cells with specific characteristics (CD3+, CD8+, CD45RA-, CD62L-), then sequences their TCR genes to identify high affinity clones that recognize tumor antigens while avoiding central tolerance elimination

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent uses flow cytometry as an intermediary tool to bridge the gap between central tolerance mechanisms and peripheral T cell selection, enabling identification of high affinity TCRs that survived central tolerance screening but remain effective against tumor antigens

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If TCRs with high affinity for tumor antigens are isolated, then adoptive immunotherapy effectiveness is improved, but the diversity of malignancies that can be targeted is limited

Engineering Contradiction:

Improveeffectiveness of adoptive immunotherapyVSAvoiddiversity of targetable malignancies

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent identifies TCRs with broad specificity for WT1 protein, a tumor-associated antigen expressed in multiple cancer types including leukemia, lymphoma, and solid tumors. This universal TCR can target diverse malignancies through a single therapeutic approach, enabling one TCR design to address multiple cancer types rather than requiring separate TCRs for each malignancy

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Quantity of substance

If high-throughput sequencing is used to identify TCRs, then the number of TCRs with high functional avidity is increased, but the complexity of the identification process is increased

Engineering Contradiction:

Improvenumber of TCRs with high functional avidityVSAvoidcomplexity of identification process

Core Design Contradiction:

Quantity of substanceVSDevice complexity

Solution Approach 1:

The patent segments the complex identification process into distinct sequential steps: (1) flow cytometry-based isolation of T cells with specific surface characteristics, (2) extraction and sequencing of TCR genes, (3) bioinformatic analysis to identify high affinity clones, and (4) functional validation through tetramer staining. This segmentation makes the high-throughput process manageable and reproducible

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS12448430B2High avidity WT1 T cell receptors and uses thereof

Publication Date: 2025.10.21 FRED HUTCHINSON CANCER CENT

AI summary

The present disclosure provides T cell receptors (TCRs) and related binding proteins with high functional avidity against tumor associated antigen p37 from Wilms tumor protein 1 (WT1), T cells expressing such high affinity WT1 specific TCRs, nucleic acids encoding the same, and compositions for use in treating diseases or disorders in which cells overexpress WT1 and/or produce the p37 antigen, such as in cancer.