Antibody Variable Domain De-immunization via Interface Residue Substitution
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Solution Overview
Problem
Current methods to reduce the immunogenicity of therapeutic antibodies, particularly antibody variable domains, are either ineffective or come with adverse effects, such as immune system damage, and lack straightforward solutions for extensively reducing B-cell epitopes without extensive molecular modeling.
Innovation Solution
Substituting specific amino acid residues at the interface between variable and constant chains of antibody variable domains, such as Leucine (L), Valine (V), Aspartic acid (D), Phenylalanine (F), Arginine (R), and Glutamic Acid (E), with less immunogenic amino acids like Serine (S) and Threonine (T), particularly at positions 12, 99, 101, 103, 144, and 148, to decrease immunogenicity without affecting thermal stability or binding activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If amino acid residues at the interface between variable and constant chains are substituted with less immunogenic amino acids, then immunogenicity is reduced, but binding activity and thermal stability must be maintained
Solution Approach 1:
The patent applies local quality by specifically targeting amino acid residues at the interface between variable and constant chains for substitution, while leaving other regions unchanged. This localized approach reduces immunogenicity at the critical interface region without affecting the overall binding activity and thermal stability of the antibody variable domain
Solution Approach 2:
The patent changes the chemical parameters of amino acid residues by substituting hydrophobic residues (Leucine, Valine, Phenylalanine) with less immunogenic alternatives (Serine, Threonine). This parameter change reduces B-cell epitope exposure while maintaining the structural integrity and functional properties of the antibody
2Object-affected harmful factors
If amino acid substitution is performed to reduce B-cell epitopes, then immunogenicity decreases, but extensive molecular modeling is required
Solution Approach 1:
The patent performs preliminary action by pre-identifying target amino acid residues based on their location at the variable-constant chain interface and their hydrophobic character. This preliminary identification provides a straightforward basis for substitution without requiring extensive molecular modeling or computational simulations to locate epitopes
Solution Approach 2:
The patent segments the antibody variable domain by focusing specifically on the interface region between variable and constant chains. This segmentation allows targeted substitution of amino acid residues at this specific location, simplifying the de-immunization process compared to analyzing the entire antibody structure
3Object-affected harmful factors
If hydrophobic amino acids are substituted to reduce immunogenicity, then B-cell epitope exposure is minimized, but structural stability must be maintained
Solution Approach 1:
The patent changes the physicochemical parameters of amino acid residues by substituting hydrophobic residues with polar residues (Serine, Threonine). This parameter change reduces hydrophobic surface area and B-cell epitope exposure while the careful selection of substitution positions at the variable-constant interface maintains the overall structural stability and thermal properties of the antibody variable domain
Data Source
AI summary
A method for decreasing the immunogenicity of antibody variable domains is disclosed.