TREM2 Binding Molecule Inhibits Cleavage to Preserve Microglial Function

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current therapeutic approaches fail to effectively treat and prevent neurodegenerative disorders, such as Alzheimer's disease, due to the lack of means to inhibit the cleavage of the triggering receptor expressed on myeloid cells 2 (TREM2), which leads to reduced phagocytic activity and accumulation of amyloid plaques.

Innovation Solution

A binding molecule with a specific binding site within the ectodomain of TREM2 is developed to inhibit its cleavage, particularly at the C-terminal to histidine 157, thereby stabilizing surface-bound TREM2 and enhancing microglial activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If TREM2 cleavage is allowed to proceed naturally, then soluble TREM2 is released and can be detected in CSF, but membrane-bound TREM2 levels decrease leading to reduced microglial phagocytic activity

Engineering Contradiction:

Improvesoluble TREM2VSAvoidmicroglial phagocytic activity

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The binding molecule acts as an intermediary that blocks the interaction between TREM2 and metalloproteinases, preventing cleavage. This mediator approach allows the system to maintain membrane-bound TREM2 levels while avoiding the harmful effect of reduced phagocytic activity that would result from uncontrolled cleavage

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The binding molecule applies preliminary anti-action by preemptively blocking the cleavage site or preventing metalloproteinase access to TREM2 before cleavage can occur. This prevents the formation of soluble TREM2 and maintains full-length membrane-bound TREM2, thereby preserving microglial function

Inventive Principle:

Principle #9Preliminary anti-action

2Quantity of substance

If metalloproteinases cleave TREM2, then soluble TREM2 is produced and secreted, but the accumulation of amyloid plaques increases due to reduced clearance

Engineering Contradiction:

Improvesoluble TREM2VSAvoidamyloid plaque accumulation

Core Design Contradiction:

Quantity of substanceVSObject-generated harmful factors

Solution Approach 1:

The binding molecule serves as an intermediary that intercepts the cleavage process, preventing the conversion of membrane-bound TREM2 to soluble form. By blocking this conversion, the molecule prevents the loss of phagocytic capacity that would otherwise lead to amyloid plaque accumulation

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention converts the potentially harmful effect of TREM2 cleavage (which leads to plaque accumulation) into a beneficial outcome by using the binding molecule to block cleavage. This maintains TREM2 in its functional membrane-bound state, enhancing plaque clearance capabilities

Inventive Principle:

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

Data Source

PatentUS10941200B2TREM2 cleavage modulators and uses thereof

Publication Date: 2021.03.09 DEUT ZENT FUER NEURODEGENERATIVE ERKRANKUNGEN EV

AI summary

The present invention relates to a binding molecule having a binding site within the ectodomain of the triggering receptor expressed on myeloid cells 2 (TREM2), wherein the binding molecule inhibits TREM2 cleavage. Said binding molecule is particularly useful for treating and/or preventing a neurological disorder, such as a neurodegenerative disorder. Also encompassed by the present invention is a pharmaceutical composition for use in treating and/or preventing a neurological disorder, wherein the pharmaceutical composition comprises the binding molecule of the present invention. Neurodegenerative disorders that may be treated and/or prevented by using the binding molecule of the present invention include Alzheimer's disease (AD), Frontotemporal lobar degeneration (FTLD), FTLD-like syndrome, Parkinson's disease, Nasu-Hakola disease, Multiple sclerosis (MS), Huntington disease, immune-mediated neuropathies, or Amyotrophic lateral sclerosis (ALS).