MAGE-A3 TCRs Using HLA Class II for Expanded Cancer Eligibility

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Solution Overview

Problem

Adoptive cell therapy using T-cells that target HLA-A*02 restricted T-cell epitopes is limited to patients expressing HLA-A*02, excluding a significant portion of the population, necessitating improved immunological compositions and methods for treating cancer.

Innovation Solution

Development of T-cell receptors (TCRs) with antigenic specificity for MAGE-A3 and MAGE-A6, recognizing these antigens in the context of HLA-DPβ1*04, enabling treatment of a broader patient population, including those lacking HLA-A*02 expression.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If T-cells targeting HLA-A*02 restricted epitopes are used, then tumor regression is achieved in some patients, but treatment is limited to HLA-A*02 expressing patients

Engineering Contradiction:

Improvetumor regression efficacyVSAvoidpatient population coverage

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent develops TCRs that recognize MAGE-A3 antigen presented by multiple HLA class II molecules (HLA-DPβ1*04, HLA-DQβ1*03, HLA-DRβ1*01), enabling a single TCR construct to treat patients with different HLA backgrounds. This multi-functionality expands patient eligibility from only HLA-A*02 expressers to a broader population including HLA class II expressers.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The invention changes the target parameter from HLA class I restricted epitopes (HLA-A*02) to HLA class II restricted epitopes (MAGE-A3 with HLA-DPβ1*04, HLA-DQβ1*03, or HLA-DRβ1*01). This parameter change in MHC restriction allows treatment of patients who lack HLA-A*02 but express alternative HLA class II alleles.

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If TCRs targeting MAGE-A3 in context of HLA-DPβ1*04 are developed, then patient population coverage is expanded, but complexity of immunological composition increases

Engineering Contradiction:

Improvepatient population coverageVSAvoidimmunological composition complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent segments the immunological composition into distinct components: isolated TCR alpha and beta chains with defined variable regions, or TCR-beta chains paired with endogenous TCR-alpha chains. This segmentation allows modular design and selection of appropriate TCR components for different patient HLA backgrounds without requiring entirely new composition designs.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent uses TCRs as intermediary molecules that bridge the gap between T-cells and MAGE-A3 antigen presented by various HLA class II molecules. These TCR intermediaries enable specific recognition and binding across different HLA backgrounds, simplifying the overall immunological interaction while expanding patient coverage.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS12404317B2T cell receptors recognizing MHC class II-restricted MAGE-A3

Publication Date: 2025.09.02 THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY DEPARTMENT OF HEALTH & HUMAN SERVICES

AI summary

The invention provides an isolated or purified T-cell receptor (TCR) having antigenic specificity for MHC Class II-restricted MAGE-A3. The invention further provides related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, and populations of cells. Further provided by the invention are antibodies, or an antigen binding portion thereof, and pharmaceutical compositions relating to the TCRs of the invention. Methods of detecting the presence of cancer in a host and methods of treating or preventing cancer in a mammal are further provided by the invention.