Antibody-Affinity Compounds for Regioselective ADC Labeling
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Solution Overview
Problem
Existing antibody-drug conjugates (ADCs) face issues with nonuniform drug-to-antibody ratios (DAR) and unpredictable conjugation positions, leading to variations in pharmacokinetics and drug release rates, which current genetic engineering methods struggle to control efficiently.
Innovation Solution
A compound with an affinity substance and a bioorthogonal functional group is used to chemically modify antibodies, allowing for regioselective conjugation without peptide linkers, controlling the number and position of drug attachment through a chemical synthetic technique.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If random conjugation method is used to attach drug to antibody, then drug-to-antibody ratio (DAR) ranges from 0 to 8 with multiple conjugation positions, but this results in nonuniform ADC composition and unpredictable pharmacokinetics
Solution Approach 1:
The patent introduces a peptide reagent as an intermediary substance that contains both an NHS-activated ester for antibody binding and a bioorthogonal functional group for subsequent drug attachment. This intermediary enables controlled, regioselective modification of specific antibody residues (Lys246, Lys248, Lys288, or Lys290 in the Fc region) while maintaining a defined drug-to-antibody ratio, thereby resolving the contradiction between versatility in DAR control and precision in conjugation position uniformity
Solution Approach 2:
The invention applies local quality by enabling site-specific modification of antibody Fc region lysine residues through the peptide reagent. Instead of random conjugation across multiple antibody sites, the method targets specific local regions (Fc region residues 246-290), achieving uniform conjugation positions with controlled DAR values (preferably 1 or 2), thus simultaneously improving both adaptability and manufacturing precision
2Manufacturing precision
If genetic engineering methods are used to achieve regioselective antibody modification, then conjugation position and number can be controlled, but this reduces antibody expression efficiency and total yield
Solution Approach 1:
The patent replaces the genetic engineering approach (biological system) with a chemical conjugation method using NHS-activated ester chemistry. This substitution allows regioselective modification of antibody Fc region lysine residues through chemical reactions rather than genetic manipulation, thereby maintaining high antibody expression efficiency and total yield while achieving the desired manufacturing precision in conjugation position and number control
3Manufacturing precision
If peptide linkers are used in antibody-drug conjugates, then regioselective modification can be achieved, but this introduces immunogenicity and hydrolysis problems
Solution Approach 1:
The invention extracts and eliminates the peptide linker component from the ADC structure. By using NHS-activated ester chemistry to directly conjugate the drug to antibody Fc region lysine residues through the peptide reagent intermediary, the method achieves regioselective modification without incorporating peptide linkers that would introduce immunogenicity and hydrolysis vulnerabilities, thereby removing the harmful factors while preserving manufacturing precision
Solution Approach 2:
The patent changes the chemical parameters of the conjugation method by using NHS-activated ester chemistry with bioorthogonal functional groups instead of traditional peptide linker-based approaches. This parameter change enables stable, non-immunogenic conjugation that resists hydrolysis while maintaining the ability to achieve regioselective modification at controlled DAR values
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This method achieves controlled drug-to-antibody ratios and specific conjugation sites, enhancing the consistency and efficacy of ADCs by avoiding peptide-related immunogenicity and hydrolysis issues.
Implementation Method 1
E is a divalent group comprising an electrophilic group (i) coupled with the leaving group and (ii) having ability to react with a nucleophilic group in the antibody
Data Source
AI summary
Compounds having an affinity substance to an antibody and a bioorthogonal functional group, represented by the following Formula (I):whereinA is an affinity substance to an antibody,L is a divalent group comprising a leaving group,E is a divalent group comprising an electrophilic group (i) coupled with the leaving group and (ii) having ability to react with a nucleophilic group in the antibody,B is a bioorthogonal functional group, andthe leaving group has ability to be cleaved and eliminated from E by a reaction between the nucleophilic group and the electrophilic group, or a salt thereof, and the like are useful for labelling antibodies.