Misfolded TDP-43 Selective Antibodies via Conformational Epitopes

Solution Overview

Problem

Current antibodies targeting TDP-43 are not selective for misfolded forms, risking binding to native, functional TDP-43 and potentially being fatal, as misfolded TDP-43 is elusive due to low concentration and essential for embryonic development.

Innovation Solution

Development of conformational epitopes, specifically TTEQ or related peptides, in cyclic compounds that are selectively exposed in misfolded TDP-43, allowing for the creation of antibodies that bind preferentially to these epitopes rather than native TDP-43, using computational simulations and molecular dynamics to identify exposed regions in misfolded proteins.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If antibodies target TDP-43 to treat ALS and FTD, then pathogenic misfolded forms can be eliminated, but native functional TDP-43 may be bound and harmed

Engineering Contradiction:

Improveselectivity for misfolded TDP-43VSAvoidbinding to native TDP-43

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent identifies and targets a specific local region (epitope) within the TDP-43 protein that is conformationally distinct in misfolded forms compared to native forms. By focusing the antibody binding site on this specific local structure rather than the entire protein, selectivity is achieved without affecting native TDP-43 function.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent exploits conformational changes in the epitope region between misfolded and native TDP-43 states. Antibodies are designed to recognize specific conformational parameters (three-dimensional structure, spatial arrangement) that differ between pathogenic and functional forms, enabling selective binding based on structural parameter changes.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If antibodies bind to misfolded TDP-43, then pathogenic inclusions can be targeted, but misfolded TDP-43 is elusive due to low concentration

Engineering Contradiction:

Improvebinding to misfolded TDP-43VSAvoiddetectability of misfolded TDP-43

Core Design Contradiction:

ReliabilityVSDifficulty of detecting and measuring

Solution Approach 1:

The patent employs computational simulations and molecular dynamics modeling to predict and identify conformational epitopes in misfolded TDP-43 before experimental validation. This preliminary computational action facilitates the design of antibodies that can detect and bind to the elusive misfolded form, overcoming the difficulty of detection due to low concentration.

Inventive Principle:

Principle #10Preliminary action

3Reliability

If conventional antibodies target TDP-43, then treatment can be administered, but the essential role of TDP-43 in embryonic development creates risk

Engineering Contradiction:

Improvespecificity for pathogenic formsVSAvoidimpact on healthy cells

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent identifies and targets a specific local region (epitope) within the TDP-43 protein that is conformationally distinct in misfolded forms compared to native forms. By focusing the antibody binding site on this specific local structure rather than the entire protein, selectivity is achieved without affecting native TDP-43 function.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent exploits conformational changes in the epitope region between misfolded and native TDP-43 states. Antibodies are designed to recognize specific conformational parameters (three-dimensional structure, spatial arrangement) that differ between pathogenic and functional forms, enabling selective binding based on structural parameter changes.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20220162293A1Epitopes in the RNA recognition motif 1 (RRM1) of TDP-43 and misfolding-selective antibodies thereto

Publication Date: 2022.05.26 THE UNIV OF BRITISH COLUMBIA

AI summary

The disclosure pertains to conformational epitopes in TDP-43, antibodies thereto and methods of making and using immunogens and antibodies specific thereto.