Self-Immolative Linker for Antibody-Drug Conjugates
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Solution Overview
Problem
Current antibody-drug conjugate linkers face stability issues in circulation and within cells, leading to inefficient drug release in cancer cells, with existing linkers either being unstable in acidic environments or causing systemic toxicity.
Innovation Solution
Development of compounds with a self-immolative group, specifically a linker comprising a glucuronic acid moiety or derivative, an electron withdrawing group, and an isoprenyl derivative unit, which is stable in blood and plasma, allowing for targeted drug release in cancer cells through enzymatic hydrolysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a thioether linker is used in antibody-drug conjugates, then the drug can be delivered to target cells, but the linker shows instability due to reverse reaction in the bonding method
Solution Approach 1:
The patent changes the chemical parameters of the linker by introducing a self-immolative group with specific structural features (electron-withdrawing group, leaving group) that fundamentally alter the stability profile. This transforms the linker from being prone to reverse reaction to being stable in circulation but cleavable in target cells through enzymatic hydrolysis followed by self-immolation.
Solution Approach 2:
The patent creates a composite linker structure combining multiple functional elements: a stable connecting portion, a self-immolative group with electron-withdrawing moiety, and a leaving group. This composite structure achieves both circulation stability and targeted drug release, resolving the contradiction between stability and controlled release.
2Reliability
If a disulfide linker is used to separate drug in cells, then drug dissociation is achieved through thiol exchange reaction, but drug may be separated during circulation due to presence of various thiols
Solution Approach 1:
The patent applies local quality by designing the linker with differentiated regions: a stable connecting portion that resists cleavage in circulation, and a self-immolative portion with electron-withdrawing group that becomes labile after enzymatic triggering. This spatial differentiation of stability properties prevents premature drug separation while ensuring efficient release in target cells.
Solution Approach 2:
The self-immolative group acts as an intermediary between the stable linker and the drug payload. After enzymatic cleavage of the connecting portion, this intermediary undergoes self-immolation to release the drug, preventing direct exposure to circulating thiols while enabling controlled release in target cells.
3Reliability
If a hydrazone linker is used for chemical separation, then the linker is stable in blood, but it is rapidly hydrolyzed in acidic environments of cells, endosomes, or lysosomes
Solution Approach 1:
The patent implements self-service through the self-immolative group that automatically undergoes intramolecular reaction after enzymatic cleavage. The electron-withdrawing group facilitates spontaneous decomposition and drug release without requiring additional external triggers, enabling rapid drug release in target cells while maintaining circulation stability.
Solution Approach 2:
The patent replaces the acid-catalyzed hydrolysis mechanism of hydrazone linkers with an enzyme-triggered self-immolation mechanism. This substitution maintains circulation stability (avoiding acid-catalyzed breakdown) while enabling controlled, rapid drug release through enzymatic recognition followed by spontaneous self-immolation.
4Reliability
If a peptide linker is used for enzyme hydrolysis, then the linker is stable in blood, but it has hydrophobicity causing aggregation of antibody-drug conjugates
Solution Approach 1:
The patent changes the physicochemical parameters of the linker by incorporating hydrophilic self-immolative groups with electron-withdrawing moieties. This modification maintains enzyme recognition and stability in blood while reducing hydrophobicity-induced aggregation, improving the overall physicochemical properties of the antibody-drug conjugate.
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 self-immolative linker enhances the stability of antibody-drug conjugates in circulation and ensures specific drug release in cancer cells, improving therapeutic efficacy while minimizing systemic toxicity.
Implementation Method 1
allowing for targeted drug release in cancer cells through enzymatic hydrolysis
Data Source
AI summary
Provided herein are compounds comprising a self-immolative group, and the compounds comprising a self-immolative group according to the present invention may include a protein (for example, an oligopeptide, a polypeptide, an antibody, or the like) having substrate-specificity for a target and an active agent (for example, a drug, a toxin, a ligand, a detection probe, or the like) having a specific function or activity.