Transmembrane TNF Agonist for T Cell Precursor Generation

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Solution Overview

Problem

Current methods for generating T cell precursors from hematopoietic stem and progenitor cells in vitro are limited by the need for optimal cytokine doses and durations, with soluble TNF (sTNF) enhancing generation but promoting differentiation at the expense of self-renewal, and the mechanisms of TNF receptor activation are not fully understood.

Innovation Solution

Activating tumor necrosis factor receptor 2 (TNFR2) using transmembrane TNF (tmTNF) in an artificial thymic organoid system, where stromal cells express tmTNF and Notch ligands, to maximize T cell precursor generation while maintaining a pool of undifferentiated hematopoietic stem and progenitor cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If soluble TNF (sTNF) is used to enhance T cell precursor generation, then the yield of T cell precursors increases, but hematopoietic stem and progenitor cell self-renewal is compromised due to accelerated differentiation

Engineering Contradiction:

Improveyield of T cell precursorsVSAvoidself-renewal capacity of HSPCs

Core Design Contradiction:

ProductivityVSStability of the object's composition

Solution Approach 1:

The patent changes the molecular form of TNF from soluble to transmembrane, and selectively targets TNFR2 instead of TNFR1. This parameter change in receptor specificity allows enhancement of T cell precursor generation while preserving HSPC self-renewal capacity, resolving the contradiction between productivity and stability.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces transmembrane TNF as an intermediary that selectively activates TNFR2 signaling pathway. This intermediary enables differentiated T cell precursor generation without triggering the differentiation-promoting TNFR1 pathway, thus maintaining the balance between productivity and self-renewal.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If TNF signaling is activated to promote T cell precursor differentiation, then T cell precursor generation is enhanced, but the mechanism is not fully understood and optimal conditions vary

Engineering Contradiction:

ImproveT cell precursor generationVSAvoidmechanistic understanding

Core Design Contradiction:

ProductivityVSLoss of information

Solution Approach 1:

The patent segments the TNF signaling system by selectively activating TNFR2 while leaving TNFR1 untouched. This segmentation allows independent optimization of TNFR2-mediated T cell precursor generation without the confounding effects of TNFR1 activation, thereby enhancing productivity while clarifying the specific mechanistic role of TNFR2.

Inventive Principle:

Principle #1Segmentation

3Speed

If sTNF is applied to accelerate HSPC differentiation into T cell precursors, then differentiation speed increases, but the optimal dose and duration are not well-defined

Engineering Contradiction:

Improvedifferentiation rateVSAvoidoptimization parameters

Core Design Contradiction:

SpeedVSDevice complexity

Solution Approach 1:

The patent extracts the differentiating effect from the complex sTNF system and isolates it to transmembrane TNF acting specifically on TNFR2. This extraction eliminates the need for optimizing multiple parameters (dose, duration, solubility) associated with sTNF, simplifying the system while maintaining accelerated differentiation speed.

Inventive Principle:

Principle #2Taking out (Extraction)

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

This approach significantly increases the yield of T cell precursors per hematopoietic stem and progenitor cell, maintaining their undifferentiated state and improving their development potential, with selective targeting of TNFR2 avoiding aberrant activation of TNFR1, thus enhancing T cell precursor generation and quality.

Implementation Method 1

tmTNF and sTNF can bind to and activate TNF receptor 1 (TNFR1, also known as CD120a). However, only tmTNF is capable to activate TNF receptor 2 (TNFR2, also known as CD120b)

Methodology Applied

Scientific EffectReceptor-ligand binding:

Data Source

PatentUS20240240144A1Generating t cell precursors via agonizing tumor necrosis factor receptor 2

Publication Date: 2024.07.18 UNIV GENT

AI summary

This disclosure relates to methods and systems for generating T cell precursors from hematopoietic stem and progenitor cells (HSPCs) in vitro. This disclosure discloses that—besides activation of the Notch signaling pathway—activation of tumor necrosis factor receptor 2 (TNFR2) present on the HSPCs is crucial to maximize the generation of T cell precursors. Hence, this disclosure relates to methods and systems, such as artificial thymic organoid systems, wherein agonists for TNFR2, such as transmembrane tumor necrosis factor (tmTNF), are used to maximally generate T cell precursors. The latter T cell precursors are useful for immune reconstitution due to transplantation or immunodeficiency disorders and may be used to generate off-the-shelf chimeric antigen receptor T cells or T cell receptor engineered T cells for immunotherapeutic purposes.