Tri-TAC T Cell Antigen Coupler MHC-Mediated Signaling

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Solution Overview

Problem

Current T cell therapies for cancer, such as CAR-engineered T cells, face challenges with optimal activation and safety due to synthetic receptor structures that may lead to off-target toxicities and loss of antigen specificity.

Innovation Solution

Development of Trifunctional T cell Antigen Couplers (Tri-TACs) that redirect T cells to attack tumors using a native TCR signaling structure, recruiting the T-cell receptor in combination with co-receptor stimulation, thereby enhancing activity and safety.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CAR-engineered T cells are used for cancer therapy, then T cell activation and tumor targeting are achieved, but off-target toxicities and loss of antigen specificity occur

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidoff-target toxicities

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent segments the T cell activation process into two distinct components: a TCR-specific component that recognizes MHC-presented antigens and a co-receptor component (CD3 or CD28) that provides additional activation signals. This segmentation allows the TAC to engage native TCR signaling pathways while maintaining specificity, thereby reducing off-target effects compared to CAR approaches that use synthetic signaling domains.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent introduces MHC molecules as an intermediary layer between the TAC and the T cell receptor. The TAC engages the TCR through MHC-presented antigens, which acts as a natural intermediary that ensures specific recognition and activation only when the appropriate antigen-MHC complex is formed. This intermediary mechanism prevents off-target activation while maintaining therapeutic efficacy.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Adaptability or versatility

If synthetic receptor structures are used in T cell therapy, then tumor targeting capability is achieved, but antigen specificity is lost

Engineering Contradiction:

Improvetumor targeting capabilityVSAvoidantigen specificity

Core Design Contradiction:

Adaptability or versatilityVSMeasurement precision

Solution Approach 1:

Instead of using synthetic receptors that directly bind tumor antigens (CAR approach), the patent inverts the approach by using a TAC that engages the natural TCR-MHC antigen recognition pathway. The TAC is designed to be recognized by the TCR in the context of MHC presentation, thereby utilizing the body's own highly specific antigen recognition system rather than replacing it with synthetic binding domains.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent changes the fundamental parameter of receptor-antigen interaction from direct binding (CAR) to MHC-mediated recognition (TAC). This parameter change leverages the natural specificity of the TCR-MHC-antigen triad, ensuring that tumor targeting is achieved through the highly specific recognition of tumor-associated antigens presented by MHC molecules, thereby maintaining antigen specificity while achieving tumor targeting capability.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If TCR signaling structure is used in Tri-TACs, then safety and activity are enhanced, but structural complexity increases

Engineering Contradiction:

Improvesafety and activityVSAvoidreceptor structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent employs universal T cell signaling components (TCR, CD3, or CD28) that already possess well-characterized signaling pathways and functions. By using these universal, naturally occurring components rather than designing entirely new synthetic signaling domains, the patent achieves enhanced safety and activity through native signaling while avoiding the complexity of creating de novo signaling structures. The multi-functionality of these universal components (antigen recognition, co-stimulation, signal transduction) is leveraged to simplify the overall design.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

Tri-TACs demonstrate enhanced activity and safety by activating natural Major Histocompatibility complex signaling through the T-cell receptor while maintaining MHC-unrestricted targeting, potentially reducing off-target effects and improving therapeutic efficacy.

Implementation Method 1

a first polynucleotide encoding a ligand that selectively binds a CD19 antigen

Methodology Applied

Scientific EffectAntigen-antibody binding:

Implementation Method 2

a second polynucleotide encoding a UCHT1 ligand that binds CD3

Methodology Applied

Scientific EffectProtein-protein binding:

Implementation Method 3

a third polynucleotide encoding a TCR signaling domain polypeptide comprising a cytosolic domain and a transmembrane domain

Methodology Applied

Scientific EffectSignal transduction:

Data Source

PatentUS11878035B2T cell-antigen coupler with various construct optimizations

Publication Date: 2024.01.23 TRIUMVIRA IMMUNOLOGICS USA INC

AI summary

A trifunctional molecule is provided, comprising (i) a target-specific ligand, (ii) a ligand that binds a protein associated with a TCR complex, and (iii) a T cell receptor signaling domain polypeptide. Variants of the molecule are provided, including variants that exhibit optimized surface expression, transduction efficiency, and effector functionality. Variations include, for example, different ligands that bind CD3 epsilon (e.g., OKT3, L2K, F6A, UCHT1 and humanized UCHT1), different signaling domains, and different linkers between domains.