Antibody Drug Conjugate Linker Platform With Stable Sulfur Bridges
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Solution Overview
Problem
Existing antibody drug conjugates (ADCs) face issues with stability due to hydrolysis of amide bonds under enzymatic conditions and reversible thiol-maleimide reactions, leading to premature deconjugation and off-target toxicity.
Innovation Solution
Development of novel ADC platforms with improved conjugation methods that utilize specific coupling sites, such as cysteine residues, to form stable sulfur bridge bonds, enhancing resistance to deconjugation in plasma.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If amide bonds are used to couple linkers to lysine residues in antibodies, then coupling is achieved, but the bonds are prone to hydrolysis under enzymatic conditions leading to deconjugation
Solution Approach 1:
The patent changes the chemical parameter of the bond type from amide bond to sulfur bridge bond, and changes the coupling site parameter from lysine residues to cysteine residues. This parameter change transforms the bond from being prone to hydrolysis to being resistant to deconjugation under physiological conditions.
Solution Approach 2:
The patent utilizes the natural disulfide bond structure in antibodies, which can be reduced to free sulfhydryl groups. Instead of viewing the reducibility of disulfide bonds as a weakness, the invention converts it into a beneficial feature by forming stable sulfur bridge bonds that are resistant to hydrolysis and deconjugation.
2Ease of manufacture
If maleimide functional groups are used to couple with cysteine sulfhydryl groups, then coupling is achieved, but the reaction is reversible leading to maleimide transfer to other thiols
Solution Approach 1:
The patent extracts the problematic reversible maleimide-thiol reaction from the system and replaces it with a different coupling mechanism. By removing the maleimide functional group and using alternative coupling chemistry, the invention eliminates the source of maleimide transfer to plasma proteins like serum albumin.
Solution Approach 2:
The patent introduces an intermediary coupling mechanism that forms stable sulfur bridge bonds without relying on the reversible maleimide-thiol reaction. This intermediary approach uses alternative chemistry that maintains coupling efficiency while preventing off-target maleimide transfer.
3Manufacturing precision
If site-specific coupling to lysine residues is used, then coupling precision is achieved, but enzymatic hydrolysis causes premature deconjugation
Solution Approach 1:
The patent changes two critical parameters: the coupling site parameter from lysine residues to cysteine residues, and the bond type parameter from amide bond to sulfur bridge bond. These parameter changes maintain site-specific coupling precision while dramatically improving conjugate stability against enzymatic hydrolysis.
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 new ADC platforms demonstrate increased stability and reduced off-target toxicity, ensuring targeted delivery of bioactive molecules to cells.
Implementation Method 1
The disulfide bonds in the antibody can be broken to provide multiple free sulfhydryl groups as coupling sites. One method of coupling with the antibody sulfhydryl groups is a Michael addition reaction between the free sulfhydryl groups and an electrophilic maleimide functional group, or two Michael addition reactions between a specific substrate and free sulfhydryl groups of the antibody to form a sulfur bridge bond in a unique structure.
Data Source
AI summary
The present disclosure provides antibody drug conjugate platforms comprising a conjugator assembly component, and antibody drug conjugates comprising platform-derived linker-payloads and antibodies or antigen-binding fragments thereof. In some embodiments, an antibody drug conjugate is of the following formulaor a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, wherein values for the variables (e.g., BA, U, V, A, a′, W, w′, Y, y′, PA, x) are as described herein.