Modified Proteins Reducing Autoantibody Binding via C-Terminal Extensions
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Pre-existing autoantibodies in humans can bind to therapeutic proteins and peptides, affecting their efficacy and causing administration reactions, hypersensitivity, and altered bioavailability.
Innovation Solution
Development of modified proteins and peptides with reduced ability to bind to pre-existing antibodies, achieved through C-terminal additions, extensions, or tags, and specific amino acid substitutions, which alter the three-dimensional conformation of the dAb C-terminus.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic proteins and peptides are administered to treat diseases, then therapeutic efficacy is improved, but pre-existing autoantibodies bind to these molecules causing administration reactions, hypersensitivity, and altered bioavailability
Solution Approach 1:
The patent applies parameter changes by modifying the three-dimensional conformation of the dAb C-terminus through C-terminal additions, extensions, or tags, and specific amino acid substitutions. These structural parameter changes alter the epitope recognition, reducing binding affinity to pre-existing autoantibodies while preserving therapeutic function.
Solution Approach 2:
The invention applies local quality by making specific localized modifications at the C-terminal region of the dAb molecule. The modifications are confined to specific positions (C-terminal additions, extensions, or tags, and amino acid substitutions) rather than altering the entire molecule, thereby maintaining overall therapeutic efficacy while reducing autoantibody binding at the specific epitope region.
2Object-affected harmful factors
If modified proteins with C-terminal additions and amino acid substitutions are developed, then binding affinity to pre-existing antibodies is reduced, but molecular structure complexity increases
Solution Approach 1:
The patent employs parameter changes by introducing specific modifications (C-terminal additions of 1-50 amino acids, extensions, tags, or specific amino acid substitutions at defined positions) that alter the molecular conformation and reduce autoantibody binding affinity, accepting increased structural complexity as a trade-off for reduced immunogenicity.
Data Source
AI summary
The present invention relates to modified proteins and peptides that have reduced ability to bind to pre-existing antibodies. Such modified protein/peptide molecules can comprise C-terminal additions, extensions or tags and/or certain amino acid substitutions. Such modified molecules (e.g. fusions and conjugates) comprise proteins, peptides, antigen binding molecules, antibodies or antibody fragments such as single variable domains e.g. human immunoglobulin (antibody) single variable domains, and also single variable domains derived from non-human sources such as a llama or camel, e.g. a VHH including a nanobody TM (described in e.g. WO 94/04678 and WO 95/04079 inter alia). The invention further relates to uses, formulations, compositions comprising such modified C terminally extended and/or amino acid substituted molecules and also to methods of production and expression of these molecules.