TREM2 IgSF-Domain Antibodies for Surface Stability and Shedding Control

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Solution Overview

Problem

Existing antibodies targeting the stalk region of TREM2 do not effectively stabilize the protein on the cell surface, leading to reduced functional activity and increased shedding, which contributes to neuroinflammatory and neurodegenerative diseases.

Innovation Solution

Development of antibodies that bind to the IgSF domain of TREM2, specifically targeting residues 19 to 132, to stabilize the protein on the cell surface, reduce ectodomain shedding, and enhance functional activities such as phagocytosis and intracellular signaling.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If antibodies target the stalk region of TREM2, then they can potentially block cleavage sites, but they fail to effectively stabilize the protein on the cell surface and increase shedding

Engineering Contradiction:

ImproveTREM2 protein stability on cell surfaceVSAvoidTREM2 ectodomain shedding

Core Design Contradiction:

Stability of the object's compositionVSLoss of substance

Solution Approach 1:

The invention segments the TREM2 protein into distinct functional regions (IgSF domain vs. stalk region) and targets the IgSF domain with antibodies, separating the binding site from the cleavage site. This segmentation allows the antibody to stabilize the protein structure without interfering with cleavage site accessibility, thereby reducing shedding while maintaining stability.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention applies local quality by specifically targeting the IgSF domain (amino acids 19-132) with antibodies, giving this region a new functional property (antibody binding site) that confers stabilization. The stalk region retains its original properties including cleavage site accessibility, allowing the antibody to stabilize without blocking cleavage.

Inventive Principle:

Principle #3Local quality

2Reliability

If antibodies bind to the IgSF domain of TREM2, then they stabilize the protein and reduce shedding, but this represents a deviation from conventional targeting of the stalk region

Engineering Contradiction:

Improvefunctional activity of TREM2VSAvoidantibody targeting strategy

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention inverts the conventional approach by targeting the IgSF domain instead of the stalk region. This inversion reveals that stabilizing antibodies can be generated by binding to the N-terminal IgSF domain rather than the C-terminal stalk region, fundamentally changing the targeting strategy while improving reliability.

Inventive Principle:

Principle #13The other way round (Inversion)

3Productivity

If TREM2 is shed from the cell surface, then soluble TREM2 is released, but this reduces functional activity and contributes to neuroinflammatory diseases

Engineering Contradiction:

Improvephagocytic capacity and intracellular signalingVSAvoidneuroinflammatory and neurodegenerative disease risk

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The invention applies preliminary anti-action by using antibodies to prevent TREM2 shedding before it occurs. The stabilizing antibodies bind to the IgSF domain and maintain TREM2 in a cell surface-bound state, preemptively blocking the shedding process and preventing the release of soluble TREM2 that would otherwise contribute to neuroinflammation.

Inventive Principle:

Principle #9Preliminary anti-action

Data Source

PatentUS20250215080A1TREM2 stabilizing antibodies

Publication Date: 2025.07.03 NOVARTIS AG

AI summary

The present invention provides antibodies that bind to and stabilize human Triggering Receptor Expressed on Myeloid cells 2 (TREM2) protein and methods of using these antibodies.