Multivalent TREM1 Ligand for Tumor Antigen Cross-Presentation

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Solution Overview

Problem

Current immunotherapies lack effective ligands that can activate TREM1 in a context-specific and immunostimulatory manner to enhance antigen presentation within suppressive tumor microenvironments, limiting the efficacy of antitumor immunity.

Innovation Solution

A recombinant multimeric calnexin-derived ligand, Tetra-CNX, selectively binds to TREM1, promoting its internalization and activating SYK-dependent signaling, thereby enhancing MHC-I and MHC-II-restricted antigen presentation by macrophages and upregulating costimulatory molecules.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional immunotherapies are used, then general immune activation is achieved, but specific TREM1-mediated antigen presentation enhancement is not realized

Engineering Contradiction:

Improveantigen presentation efficacyVSAvoidcontext-specific immunostimulation

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent introduces a recombinant multimeric calnexin-derived ligand as an intermediary molecule that specifically binds to and activates TREM1 receptors on myeloid cells. This ligand acts as a mediator between the therapeutic agent and the immune system, enabling context-specific activation of antigen presentation pathways through TREM1 signaling without requiring broad immune activation.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention employs parameter changes by engineering calnexin into a multimeric form with specific valency and structural configuration. This modification alters the binding parameters to TREM1, enabling high-affinity specific activation. The multimeric structure changes the physical and biochemical parameters of the ligand to optimize TREM1 engagement and downstream signaling efficiency.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If tumor-associated macrophages are left in their natural state, then they maintain tolerogenic phenotypes, but antigen presentation and T cell priming are suppressed

Engineering Contradiction:

ImproveT cell priming capacityVSAvoidimmunosuppressive microenvironment

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the harmful immunosuppressive function of tumor-associated macrophages into a beneficial immunostimulatory function by activating TREM1 signaling. The same macrophage population that normally suppresses immunity is reprogrammed through TREM1 activation to enhance antigen presentation and T cell priming, transforming the harmful tolerogenic phenotype into a beneficial immunostimulatory phenotype.

Inventive Principle:

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

Solution Approach 2:

The invention inverts the natural function of tumor-associated macrophages by activating TREM1, which reverses their tolerogenic programming. Instead of suppressing immune responses as they naturally do, the TREM1 activation causes macrophages to adopt an immunostimulatory phenotype, presenting antigens more effectively and priming T cells, thereby inverting their pathological role in the tumor microenvironment.

Inventive Principle:

Principle #13The other way round (Inversion)

3Productivity

If TREM1 is not activated, then myeloid cell function remains suppressed, but specific antigen presentation pathways are not enhanced

Engineering Contradiction:

Improveantigen presentation rateVSAvoidsignaling pathway activation

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent extracts and isolates the key functional element needed for TREM1 activation by using a recombinant calnexin-derived ligand. Instead of requiring complex natural ligands or multiple signaling components, the invention extracts the essential binding interface and presents it in a simplified multimeric format that specifically engages TREM1, thereby enhancing antigen presentation through a targeted approach rather than complex pathway activation.

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

Tetra-CNX reprograms tumor-associated macrophages to present tumor antigens effectively, boosting CD8+ and CD4+ T cell responses and remodeling the tumor microenvironment for enhanced antitumor immunity, with effects dependent on TREM1 signaling.

Implementation Method 1

A recombinant multimeric calnexin-derived ligand, Tetra-CNX, selectively binds to TREM1, promoting its internalization and activating SYK-dependent signaling

Methodology Applied

Scientific EffectReceptor-ligand binding: Adsorption

Data Source

PatentUS20260069658A1Engineered Ligand promotes TREM1-dependent anti-tumor immunity through cross-presentation

Publication Date: 2026.03.12 NAT YANG MING CHIAO TUNG UNIV

AI summary

The present invention provides a recombinant multivalent TREM1 agonist, termed Tetra-CNX, designed to engage and activate TREM1 on myeloid cells. The ligand comprises multiple calnexin luminal domains assembled in a multimeric configuration, enabling high-avidity receptor binding and downstream SYK-dependent signaling. Upon activation, Tetra-CNX enhances lysosomal remodeling and promotes efficient antigen uptake, processing, and presentation via MHC class I and II pathways. This invention enables improved priming of CD4+ and CD8+ T cells and facilitates immune activation in contexts requiring enhanced antigen presentation, including but not limited to cancer, infectious diseases, and vaccine responses. Pharmaceutical compositions and methods of use are provided for modulating myeloid cell function and adaptive immunity through TREM1-targeted intervention.