Tris Structure Linker for Antibody-Drug Conjugate Stability
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Solution Overview
Problem
Current antibody-drug conjugates face challenges with linker stability and drug delivery efficiency, as non-cleavable linkers are unstable and cleavable linkers may release the drug prematurely before reaching target cells, leading to reduced efficacy and increased systemic toxicity.
Innovation Solution
A ligand-drug conjugate with a tris structure linker that connects a ligand and an active agent via covalent bonds, allowing for enhanced stability and targeted drug delivery by releasing the drug only within the target cells, utilizing a trigger unit for maximum drug efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If non-cleavable linkers are used to connect antibody and drug, then the linker stability is improved, but the drug delivery efficiency deteriorates due to poor ADC internalization and inability to release drug inside cells
Solution Approach 1:
The linker is segmented into two functional parts: a stable non-cleavable portion for maintaining circulation stability and a cleavable portion (containing disulfide bond or peptide sequence) for enabling intracellular drug release. This segmentation allows the linker to simultaneously achieve both stability during circulation and controlled drug release inside target cells.
Solution Approach 2:
Different regions of the linker are assigned different properties: the extracellular portion maintains high stability to prevent premature drug release, while the intracellular portion is designed with cleavable bonds that respond to intracellular conditions (reducing environment or proteolytic enzymes) to enable drug release. This local differentiation of properties resolves the contradiction between stability and drug delivery efficiency.
2Productivity
If cleavable linkers are used to enable drug release inside cells, then the drug delivery efficiency is improved, but the linker stability deteriorates causing premature drug dissociation in blood
Solution Approach 1:
The linker is pre-designed with conditional stability: it remains stable under extracellular conditions (physiological pH, oxidizing environment) but becomes cleavable under intracellular conditions (reducing environment with glutathione, or proteolytic enzyme presence). This preliminary design of condition-dependent stability allows the linker to maintain drug integrity during circulation while enabling controlled release inside target cells.
Solution Approach 2:
The linker's stability is made parameter-dependent, responding to changes in environmental conditions (redox state, pH, enzyme presence) between extracellular and intracellular compartments. The disulfide bond or peptide sequence changes its stability parameter based on these conditions, being stable in blood but cleavable inside cells, thus resolving the contradiction between circulation stability and intracellular drug release.
3Ease of manufacture
If thiol-maleimide method is used to attach linker to antibody, then the ease of manufacture is improved, but the linker stability deteriorates resulting in drug dissociation before or after reaching target cells
Solution Approach 1:
The linker employs a composite structure combining a thioether bond (from thiol-maleimide reaction) with additional stabilizing elements such as disulfide bonds or peptide sequences. The thioether portion provides ease of conjugation to antibody cysteine residues, while the composite disulfide or peptide components provide enhanced stability and controlled cleavability, resolving the contradiction between manufacturing ease and linker stability.
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 tris structure linker enables stable circulation and targeted release of the active agent within cancer cells, improving therapeutic efficacy while minimizing systemic toxicity and side effects.
Implementation Method 1
Linkers having a disulfide bond that allows dissociation through a thiol exchange reaction depend in part on the uptake of the antibody-drug conjugate into the target cells and exposure of disulfides to the cytoplasm, a reducing environment.
Implementation Method 2
Cleavable linkers may be hydrolyzed, for example, by lysosomal enzymes.
Data Source
AI summary
The present invention relates to a ligand-drug conjugate including a ligand; a linker that is connected to the ligand by a covalent bond and has a tris structure represented by a specific structural formula; and an active agent connected to the linker by a covalent bond. In the ligand-drug conjugate, the active agent is bound by the tris structure of the linker, and thus a greater number of active agents can be connected through one linker. Accordingly, a greater number of active agents per antibody binding can be delivered to the target cell, and the drug and/or toxin can stably reach the target cell and effectively exert the drug efficacy.