Antibody Variable Domain Substitutions for Lower ADA Binding
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Solution Overview
Problem
Existing antibody variable domains exhibit significant immunogenicity due to exposure of amino acids that are typically shielded by other antibody portions, leading to binding with pre-existing anti-drug antibodies (ADAs), compromising therapeutic efficacy and safety.
Innovation Solution
Substituting specific amino acids at framework positions 101, 146, and/or 148 of antibody variable domains with small moderately hydrophilic or hydrophilic amino acids, such as alanine, serine, lysine, arginine, aspartate, glutamate, asparagine, or glutamine, to reduce binding to pre-existing ADAs, and optionally adding substitutions at positions 12 and 144 to further decrease immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If antibody fragments are used to reduce immunogenicity, then the non-human component is minimized, but amino acids that are formerly shielded become exposed and increase ADA-binding
Solution Approach 1:
The patent applies local quality by making specific framework region positions (101, 146, 148) have different amino acid properties - substituting them with small moderately hydrophilic or hydrophilic amino acids while leaving other regions unchanged. This localized modification reduces ADA-binding at critical epitope positions without affecting the overall antibody fragment structure or function.
Solution Approach 2:
The patent changes the chemical parameters (amino acid sequence, hydrophilicity, size) at specific framework positions to alter the immunogenicity profile. By changing the amino acid properties at positions 101, 146, and 148, the patent modifies the epitope characteristics to reduce recognition by pre-existing ADAs while maintaining antibody functionality.
2Object-affected harmful factors
If humanized antibodies are used to reduce immunogenicity, then non-human components are minimized, but immune response still compromises efficacy and safety
Solution Approach 1:
The patent extracts and eliminates specific problematic amino acid sequences from the framework regions that are known to bind pre-existing ADAs. By removing or modifying the amino acids at positions 101, 146, and 148, the patent extracts the immunogenic elements while preserving the rest of the humanized antibody structure that provides therapeutic efficacy.
3Object-affected harmful factors
If framework region amino acids are substituted to reduce ADA-binding, then immunogenicity decreases, but structural stability may be affected
Solution Approach 1:
The patent carefully selects amino acid substitutions that maintain structural stability by using small moderately hydrophilic or hydrophilic amino acids with similar steric and chemical properties to the original residues. This parameter change approach ensures that the framework region maintains its structural integrity while reducing ADA-binding affinity.
Data Source
AI summary
The present invention relates to antibody variable domains, which exhibit a reduced binding to pre-existing anti-drug antibodies (ADA), to antibodies comprising one or more of said antibody variable domains, and to pharmaceutical compositions comprising said antibodies. The present invention further relates to nucleic acids encoding said antibody variable domains or said antibodies, vector(s) comprising said nucleic acids, 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 a method for generating said antibody variable domains and antibodies.