Cleavable Affinity Compounds for Uniform Antibody–Drug Conjugation
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Solution Overview
Problem
Existing antibody-drug conjugates (ADCs) face issues with nonuniform drug-antibody ratios (DAR) and unpredictable drug binding positions, leading to variations in pharmacokinetics and efficacy, which current genetic engineering and chemical modification methods struggle to address effectively.
Innovation Solution
A novel compound with an affinity substance, a cleavable portion, and a reactive group, allowing for regioselective modification of antibodies without using peptide linkers, utilizing a polypeptide with a glutamine residue at the N-terminal to specifically bind to antibodies, enabling controlled drug conjugation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If random conjugation method is used to attach drug to antibody, then productivity is improved (simple process), but manufacturing precision deteriorates (nonuniform DAR and conjugation position)
Solution Approach 1:
The invention introduces a peptide tag with specific local properties (affinity for antibody Fc region) at a defined position, creating a localized modification site that ensures uniform DAR while maintaining efficient conjugation. The peptide tag serves as a predetermined anchor point that guides drug attachment to specific locations on the antibody.
Solution Approach 2:
The peptide tag is预先 attached to the antibody at a specific location before drug conjugation. This preliminary action creates a predetermined modification site that controls subsequent drug attachment, ensuring uniform DAR and consistent conjugation position while simplifying the overall process.
2Manufacturing precision
If genetic engineering modification method is used to achieve regioselective modification, then manufacturing precision is improved (controlled conjugation position), but device complexity deteriorates (complex expression system construction)
Solution Approach 1:
The invention introduces a peptide tag as an intermediary element that mediates between the antibody and the drug conjugation process. This peptide tag provides a controlled attachment site without requiring complex genetic engineering of the antibody itself, simplifying the overall system while achieving precise regioselective modification.
3Ease of manufacture
If peptide linker is used in antibody-drug conjugate, then ease of manufacture is improved (chemical synthesis), but reliability deteriorates (immunogenicity and hydrolysis)
Solution Approach 1:
The invention changes the chemical parameters of the linker by using a peptide tag with specific amino acid composition and structure. This peptide tag is designed to be resistant to hydrolysis and has reduced immunogenicity while maintaining chemical synthesis feasibility, thus improving reliability without sacrificing ease of manufacture.
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
Achieves regioselective modification of antibodies with high yield and specificity, avoiding immunogenicity and hydrolysis issues, facilitating the development of consistent and effective ADCs.
Implementation Method 1
a compound having an affinity substance (A) to an antibody
Implementation Method 2
a reactive group (R) to an amino acid residue in the antibody
Implementation Method 3
a cleavable portion (L) between the affinity substance and the reactive group
Data Source
AI summary
Compounds having an affinity substance to an antibody, a cleavable portion, and a reactive group, or a salt thereof, are represented by the following Formula (I):A-L-B—R (I)whereinA is an affinity substance to an antibody,L is a cleavable linker that is a divalent group comprising a cleavable portion,B is (a) a divalent group comprising a bioorthogonal functional group or (b) a divalent group comprising no bioorthogonal functional group, andR is a reactive group to the antibody,wherein the affinity substance to an antibody is a polypeptide comprising a glutamine residue (Q) at an N-terminal.