Antibody Variable Domains with Reduced Immunogenicity
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Solution Overview
Problem
Current antibody variable domains often exhibit significant residual immunogenicity when used in therapeutic applications, leading to increased binding with pre-existing anti-drug antibodies, which compromises their efficacy and safety.
Innovation Solution
Antibody variable domains are modified by substituting arginine at position 12 and/or glutamine at position 144, and optionally threonine at position 103, to reduce binding with pre-existing anti-drug antibodies, enhancing stability and immunogenicity reduction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibody variable domains are used in therapeutic applications, then they can bind to target antigens and provide therapeutic effects, but they exhibit significant residual immunogenicity and bind to pre-existing anti-drug antibodies, compromising efficacy and safety
Solution Approach 1:
The patent applies local quality by making specific amino acid substitutions at defined positions (12, 103, and 144) within the variable domain structure. These localized changes modify specific regions to reduce immunogenicity while preserving the overall antigen-binding function of the antibody variable domain
Solution Approach 2:
The patent changes the amino acid composition parameters at specific positions within the variable domain. By substituting particular amino acids at positions 12, 103, and 144, the patent modifies the chemical and physical properties of the variable domain to reduce its recognition by pre-existing anti-drug antibodies while maintaining therapeutic function
2Object-affected harmful factors
If amino acid substitutions are made at positions 12, 103, and 144 to reduce immunogenicity, then binding to pre-existing anti-drug antibodies decreases, but there may be impact on antigen-binding capability
Solution Approach 1:
The patent applies partial action by making substitutions at only three specific positions (12, 103, and 144) rather than throughout the entire variable domain. This targeted approach reduces immunogenicity while minimizing disruption to the overall antigen-binding function
Solution Approach 2:
The patent performs preliminary action by pre-identifying and modifying residues that are likely to be recognized by pre-existing anti-drug antibodies based on their position and properties. This proactive modification prevents immunogenic recognition before the antibody is administered therapeutically
Data Source
AI summary
The present invention relates to antibody variable domains, which exhibit a reduced binding to pre-existing anti-drug antibodies (ADA), and to antibodies comprising one or more of said antibody variable domains The present invention further relates to nucleic acid sequences encoding said antibody variable domains or said antibodies, vector(s) comprising said nucleic acid sequences, host cell(s) comprising said nucleic acids or said vector(s), and a method of producing said antibody variable domains or said multispecific antibodies. Additionally, the present invention relates to pharmaceutical compositions comprising said antibodies and to methods of use thereof.