Allosteric Single Domain Antibodies for Selective mGluR2 Modulation
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Solution Overview
Problem
Current pharmacological tools targeting metabotropic glutamate receptors (mGluRs) are non-selective and primarily orthosteric, activating multiple receptor subtypes, whereas there is a need for selective compounds that can modulate the mGluR2 subtype through allosteric mechanisms to treat neurological and psychiatric disorders.
Innovation Solution
Development of anti-mGluR2 conformational single domain antibodies (sdAbs) such as DN7, DN10, and DN13, which are highly sensitive to ligand stimulation and stabilize the active state of mGluR2, acting as positive allosteric modulators.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If orthosteric ligands are used to activate mGluRs, then receptor activation is achieved, but selectivity for mGluR2 subtype is lost and multiple subtypes are activated
Solution Approach 1:
The patent uses allosteric modulators as intermediary molecules that bind to a site distinct from the orthosteric glutamate binding site. These modulators indirectly influence receptor activation through conformational changes, enabling selective modulation of mGluR2 without activating other mGluR subtypes that share the conserved orthosteric binding domain.
Solution Approach 2:
The invention targets a specific local region (allosteric site) on the mGluR2 receptor that is unique to this subtype, rather than the conserved orthosteric site. This localized binding approach allows for subtype-specific selectivity while maintaining reliable receptor activation through allosteric mechanisms.
2Measurement precision
If conventional antibodies are used to target mGluR2, then binding is achieved, but conformational specificity and allosteric modulation capability are limited
Solution Approach 1:
The patent employs single domain antibodies with modified structural parameters compared to conventional antibodies. These sdAbs are engineered to recognize specific conformational states of mGluR2, particularly the active state, through optimized CDR regions that provide enhanced conformational specificity and enable allosteric modulation capabilities.
Solution Approach 2:
The invention uses segmented single domain antibody structures (VHH domains) that can independently bind to specific conformational epitopes on mGluR2. This segmentation allows for precise conformational recognition and the ability to stabilize specific receptor states without the complexity of full conventional antibody structures.
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
These antibodies provide a novel therapeutic approach by enhancing mGluR2 response to glutamate or agonists, potentially treating anxiety, schizophrenia, epilepsy, and other disorders associated with glutamate dysfunction without binding to the orthosteric ligand site, thus offering a selective and effective modulation of the mGluR2 subtype.
Implementation Method 1
the binding of all 3 sdAbs was found highly sensitive to ligand stimulation and are able to stabilize the active state of mGluR2 so that the single domain antibodies act as positive allosteric modulators
Data Source
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AI summary
The present invention relates to anti- metabotropic glutamate receptor subtype 2 (mGluR2) conformational single domain antibodies and uses thereof in particular in the therapeutic and diagnostic field.