ADC Linker Composition for Uniform Structure and Blood Stability
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Solution Overview
Problem
Existing methods for producing antibody-drug conjugates struggle to achieve a uniform structure and stability in blood, making it difficult to control the bonding of drugs to antibodies effectively.
Innovation Solution
A compound represented by specific formulas or its salts is used to form a linker for antibody-drug conjugates, allowing for stable and uniform structure formation through a drug-linker intermediate and antibody-drug conjugate, utilizing various cleavable linkers and specific residues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If a drug is bonded to a cysteine residue or lysine residue in an antibody via a linker, then the antibody-drug conjugate can be formed, but it is not easy to control the reaction and achieve a uniform structure
Solution Approach 1:
The patent introduces a specific linker compound as an intermediary between the drug and the antibody. This linker contains a maleimide group that reacts with thiol groups, and the reaction is facilitated by controlling the formation of drug-linker intermediates first, then conjugating to the antibody. This two-step process with a designed intermediary enables better control over the bonding reaction and achieves a uniform antibody-drug conjugate structure.
2Reliability
If the drug is loaded onto the antibody-drug conjugate, then the drug can be delivered to the target site, but the drug becomes less active while existing as an antibody-drug conjugate
Solution Approach 1:
The patent incorporates a cleavage site into the linker that is designed to be cleaved by metabolic enzymes present at the target site. This preliminary design allows the drug to remain stable and inactive during circulation as part of the antibody-drug conjugate, then becomes activated upon reaching the target site where the cleavage site is cleaved by metabolic enzymes, releasing the active drug at the appropriate time and location.
3Adaptability or versatility
If disulfide bonds between heavy chains or between light and heavy chains are cleaved to create thiol groups of cysteine, then the thiol groups can bind to maleimide groups, but the structure modification increases complexity
Solution Approach 1:
The patent segments the antibody structure by selectively cleving disulfide bonds to generate free thiol groups on cysteine residues. This segmentation allows specific regions of the antibody to be modified while leaving other regions intact. The cleaved thiol groups then serve as specific binding sites for the maleimide-containing linker, enabling controlled conjugation without requiring complete structural modification of the antibody.
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
The compound enables strong bonding of antibodies to form stable antibody-drug conjugates with uniform structures, facilitating efficient drug delivery to target sites while maintaining stability in blood.
Implementation Method 1
The compound represented by formula (I) or a salt thereof can strongly bond to an antibody to form an antibody-drug conjugate that is stable in blood
Implementation Method 2
When a cleavage site incorporated into the linker is cleaved by a metabolic enzyme that is present at the target site, a drug is released and exhibits activity corresponding to the drug
Data Source
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AI summary
The present invention provides a compound or a salt thereof for use in preparing a linker that facilitates the acquisition of an antibody-drug conjugate that has a uniform structure and that is stable in blood. Disclosed as the compound or a salt thereof is a compound represented by formula [ML-I]: wherein X is a leaving group; R1 and R2 are each independently hydrogen, C1-6 alkyl optionally substituted with one or more substituents, or C1-6 alkylene-R11 optionally substituted with one or more substituents, with the proviso that R1 and R2 are not hydrogen at the same time; or R1 and R2 together with nitrogen atoms adjacent thereto form a seven-membered ring that further contains a nitrogen atom as a ring-constituting atom, the ring further having, as a substituent, -C(=O)-C1-6 alkylene-R11 optionally substituted with one or more substituents; and R11 is COOH, SO3H, or PO3H2 or an ester group of COOH, SO3H, or PO3H2; and a salt thereof.