Self-Immolative Linker for Antibody-Drug Conjugate Stability
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Solution Overview
Problem
Current antibody-drug conjugate (ADC) linkers, particularly cleavable and non-cleavable types, face instability issues which can lead to premature drug dissociation before reaching target cancer cells, affecting the efficacy and safety of cancer treatment.
Innovation Solution
A ligand-drug conjugate design featuring a linker that includes a peptide with hydrophilic amino acids and an oxime linkage, which enhances stability and targeted drug release through enzymatic cleavage, utilizing a biomolecule reaction with a prodrug and alkoxyamine to form a covalent oxime bond.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a disulfide bond linker is used to allow dissociation via thiol exchange reaction, then the antibody-drug conjugate can release drug in reducing environment, but the drug may dissociate from the antibody prior to reaching its target due to presence of thiols in blood
Solution Approach 1:
The patent introduces a self-immolative group as an intermediary component between the antibody and the drug. This self-immolative group contains a specific peptide sequence that is recognized and cleaved by lysosomal enzymes after the ADC is internalized into the target cell. The self-immolative group then undergoes spontaneous decomposition to release the active drug, thereby mediating the transition from a stable conjugate to active drug release while preventing premature dissociation in circulation.
2Ease of manufacture
If a thiol-maleimide method is used to attach drug to antibody, then the attachment is achieved, but the antibody-drug conjugate is unstable and drug may dissociate before or after reaching target cell
Solution Approach 1:
The patent changes the chemical parameters of the linker by incorporating a self-immolative group with specific chemical properties. The self-immolative group contains a cleavable peptide bond that is stable under physiological conditions but can be selectively hydrolyzed by lysosomal enzymes at pH 5.0-5.5. This parameter change transforms the linker from one that is unstable in circulation to one that is stable in circulation but releases drug intracellularly.
3Stability of the object's composition
If non-cleavable linkers are used to attach drug to antibody, then the drug cannot dissociate prematurely, but the pendant drug generally cannot dissociate from the antibody in vivo
Solution Approach 1:
The patent segments the linker into two functional parts: a stable portion that maintains conjugate integrity in circulation and a self-immolative portion that enables intracellular drug release. The self-immolative group contains a peptide sequence that is cleaved by lysosomal enzymes, causing the linker to self-decompose and release the active drug. This segmentation allows the linker to simultaneously provide both stability and controlled release capability.
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 linker design improves the stability and targeted delivery of the drug to cancer cells, reducing off-target effects and enhancing the therapeutic efficacy of ADCs.
Implementation Method 1
The linker ideally allows the drug to exhibit an effect on a target cancer cell, e.g., after being separated from the antibody (for example, by enzyme-mediated hydrolysis)
Implementation Method 2
A disulfide linker, which allows for dissociation via a thiol exchange reaction, relies in part on the uptake of an antibody-drug conjugate into a target cell and the exposure of the disulfide to the cytosol, which is a reducing environment
Data Source
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AI summary
In some aspects, the invention relates to an antibody-drug conjugate, comprising an antibody; a linker; and an active agent. The antibody-drug conjugate may comprise a self- immolative group. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.