Bioactive Molecule Conjugates With Stable Thiol Linkage
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Solution Overview
Problem
Current bioactive molecule conjugates, such as ADCs and SMDCs, face issues with stability and targetability due to hydrolysis of amide bonds and reverse Michael additions, leading to increased toxicity and reduced efficacy against cancer cells.
Innovation Solution
A novel bioactive molecule conjugate is developed using a thiol group linkage between an antibody and a linker, forming a stable C-S bond, resulting in high coupling efficiency and a therapeutic window with improved tumor-to-plasma exposure ratio.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If amide bonds are used to link bioactive molecules to antibodies in ADCs, then the conjugate can be formed through lysine coupling, but the amide bonds are prone to hydrolysis under the action of enzymes in vivo, resulting in dissociation of bioactive molecules and antibodies before reaching target cells, increasing toxicity and reducing targetability
Solution Approach 1:
The patent changes the chemical bond type from amide bond to disulfide bond, fundamentally altering the chemical parameters of the linkage. This parameter change enables the bond to be stable in plasma (resisting hydrolysis) while remaining cleavable under reducing conditions inside cells, thus resolving the contradiction between manufacturing ease and in vivo stability.
Solution Approach 2:
The disulfide bond provides dynamic properties: it remains stable under oxidizing conditions in plasma but can be reduced and cleaved under reducing conditions in the intracellular environment. This dynamic behavior allows the conjugate to maintain stability during circulation while releasing the bioactive molecule at the target site, solving the stability-toxicity contradiction.
2Adaptability or versatility
If thiol-Michael addition methods are used to couple with sulfhydryl groups of the antibody, then multiple free sulfhydryl groups can be utilized as coupling sites, but reverse Michael additions occur in systemic circulation, resulting in toxic reactions
Solution Approach 1:
The patent employs a specially designed linker structure with a disulfide bond that acts as a protective barrier. The disulfide bond prevents reverse Michael addition in systemic circulation by creating a stable, non-reactive linkage that cannot undergo the reverse reaction, thus cushioning against toxic effects before they can occur.
Solution Approach 2:
The disulfide bond serves as an intermediary between the bioactive molecule and the antibody thiol group. This intermediary structure allows stable coupling while preventing direct interaction that would lead to reverse Michael addition and toxicity, effectively mediating the interaction in a safe manner.
3Device complexity
If small molecule ligands are used instead of antibodies in SMDCs, then the conjugate structure can be simplified, but the targetability and selective binding to tumor cell receptors are reduced
Solution Approach 1:
The patent applies the disulfide bond linkage mechanism universally, whether the targeting moiety is an antibody or a small molecule ligand. This universal application of the stable disulfide linkage allows simplified small molecule structures to achieve the same high stability and targetability as complex antibody conjugates, resolving the contradiction between structural simplicity and targetability.
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 novel conjugate achieves significantly higher tumor exposure and better therapeutic efficacy compared to existing ADCs, demonstrating enhanced cancer cell killing with reduced toxicity.
Implementation Method 1
The antibody is linked to the linker via a thiol group to form the conjugate
Implementation Method 2
The disulfide bonds in the antibody can be opened to provide multiple free sulfhydryl groups as coupling sites
Implementation Method 3
One method of coupling with the sulfhydryl groups of the antibody is Michael addition reaction between the free sulfhydryl groups of the antibody and maleimide
Data Source
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AI summary
The disclosure relates to a bioactive molecule conjugate, preparation methods and use thereof, particularly relates to a novel bioactive molecule conjugate obtained by improving coupling of the drug and the targeting moiety in an ADC or SMDC, as well as its preparation method and use in the manufacture of a medicament for the treatment of a disease associated with an abnormal cell activity.