IgSF-Binding TREM2 Antibodies for Shedding-Resistant Stabilization
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Solution Overview
Problem
Existing antibodies targeting the stalk region of TREM2 do not effectively stabilize the protein, leading to dysfunctional TREM2 expression and contributing to neuroinflammatory and neurodegenerative diseases, while antibodies targeting the IgSF region are expected to have minimal impact on cleavage prevention.
Innovation Solution
Development of antibodies that specifically bind to the IgSF domain of TREM2, stabilizing the protein on the cell surface and reducing ectodomain shedding, thereby enhancing TREM2-dependent functions such as phagocytosis and intracellular signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibodies target the stalk region of TREM2, then cleavage prevention is expected, but stabilization effect is insufficient leading to dysfunctional TREM2 expression
Solution Approach 1:
The patent changes the targeting parameter from stalk region to IgSF domain, fundamentally altering the binding location to achieve both cleavage prevention and stabilization. This parameter change resolves the contradiction by finding a new target region that provides dual functionality.
Solution Approach 2:
The patent introduces a novel antibody design that acts as an intermediary between the IgSF domain and the cleavage site, where binding to IgSF domain indirectly prevents cleavage at the stalk region. This intermediary approach resolves the contradiction by achieving cleavage prevention through a different mechanism than direct stalk region binding.
2Strength
If antibodies target the IgSF region of TREM2, then binding affinity is achieved, but cleavage prevention impact is expected to be minimal
Solution Approach 1:
The patent inverts the conventional approach by targeting the IgSF domain (typically considered the binding region) rather than the stalk region (typically considered the cleavage region). This inversion reveals that IgSF domain binding can indirectly prevent cleavage, resolving the contradiction by reversing the expected functional assignment.
Solution Approach 2:
The patent establishes a feedback mechanism where IgSF domain binding by antibodies creates conformational changes or steric effects that propagate to the stalk region, preventing cleavage. This feedback loop resolves the contradiction by showing how binding at one site can exert control at a distant site through molecular communication.
3Productivity
If TREM2 ectodomain shedding occurs, then protein turnover is maintained, but functional TREM2 expression is reduced contributing to neuroinflammatory diseases
Solution Approach 1:
The patent applies preliminary anti-action by using antibodies to preemptively block the shedding process before it occurs. By binding to the IgSF domain, the antibodies prevent the ectodomain shedding that would otherwise reduce functional TREM2 expression, thus counteracting the harmful effect before it manifests.
Solution Approach 2:
The patent takes preliminary action by stabilizing TREM2 expression through IgSF domain binding before disease pathology develops. This preliminary stabilization prevents the reduction in functional TREM2 expression that would otherwise contribute to neuroinflammatory and neurodegenerative diseases.
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
The IgSF-targeting antibodies effectively stabilize TREM2, increasing phagocytic capacity and maintaining functional TREM2 expression, offering therapeutic potential for neuroinflammatory and neurodegenerative diseases like Alzheimer's and Parkinson's.
Implementation Method 1
antibodies that bind to and stabilize human Triggering Receptor Expressed on Myeloid cells 2 (TREM2) protein
Data Source
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.