Mutant CD8 Alpha T Cells to Reduce TCR Off-Target Reactivity

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Solution Overview

Problem

Existing TCR-based cancer therapies face challenges in predicting and mitigating off-target reactivities and toxicities due to cross-reactivities with peptides having similar amino acid sequences, as evident in severe cases like MAGE-A3 TCR T cells causing cardiotoxicity.

Innovation Solution

Engineered cytotoxic T cells and CD4+ helper T cells are developed with modified CD8 alpha polypeptides and TCRs that reduce binding to MHC, using non-endogenous expression vectors and inhibitory nucleic acids to minimize off-target interactions, and are administered with pharmaceutically acceptable carriers.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If TCR-based therapies are used to target cancer antigens, then cancer treatment effectiveness is improved, but off-target reactivities and toxicities increase due to cross-reactivities with similar peptides

Engineering Contradiction:

Improvecancer treatment effectivenessVSAvoidoff-target reactivities and toxicities

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the CD8 alpha polypeptide sequence (amino acid positions 2, 3, and/or 4) to alter its binding parameters to MHC molecules. This parameter change reduces the affinity or specificity of CD8 alpha for certain MHC peptides, thereby decreasing off-target reactivities while preserving on-target cancer cell recognition and cytotoxicity.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention introduces local quality changes by mutating specific residues in the CD8 alpha polypeptide at defined positions (2, 3, and/or 4). These localized mutations confer altered binding properties to specific regions of the polypeptide, enabling selective modulation of MHC interaction without affecting the overall TCR function or other aspects of T cell biology.

Inventive Principle:

Principle #3Local quality

2Adaptability or versatility

If wild-type CD8 alpha polypeptide is expressed in T cells, then T cell function is maintained, but cross-reactivity with similar peptides leads to cardiotoxicity and other severe toxicities

Engineering Contradiction:

ImproveT cell functionVSAvoidcross-reactivity-induced toxicities

Core Design Contradiction:

Adaptability or versatilityVSObject-generated harmful factors

Solution Approach 1:

The patent changes the binding parameters of the CD8 alpha polypeptide by introducing mutations at amino acid positions 2, 3, and/or 4. This modifies the polypeptide's interaction characteristics with MHC molecules, reducing cross-reactivity with self-peptides (such as cardiac titin peptides) while maintaining necessary T cell functions for cancer target recognition.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention converts the potentially harmful cross-reactivity of wild-type CD8 alpha into a beneficial selective binding characteristic. By mutating CD8 alpha, the T cells lose non-specific cross-reactivity (the harm) while retaining specific recognition capability for cancer-associated MHC peptides (the benefit), effectively transforming a toxic property into a therapeutic advantage.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS20250302956A1Compositions and methods for modulating TCR specificity

Publication Date: 2025.10.02 MEMORIAL HOSPITAL FOR CANCER & ALLIED DISEASES

AI summary

The present technology provides compositions and methods for modulating T Cell Receptor (TCR) specificity as well as methods for treating cancer in a subject in need thereof. The present disclosure provides engineered cytotoxic T cells comprising a TCR and/or nucleic acid encoding the TCR and a mutant CD8 alpha polypeptide and/or nucleic acid encoding the mutant CD8 alpha polypeptide.