SO2 Cleavable Linker Conjugates Using Triggered Cyclization
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Solution Overview
Problem
Existing antibody-drug conjugates (ADCs) face challenges in developing linkers that provide target-specificity with high activity in tumor cells and low activity in healthy cells, necessitating improved linker components for enhanced efficacy.
Innovation Solution
The development of conjugates comprising a cleavable linker system with a targeting moiety and a triggering group that promotes intramolecular cyclization to release the active agent selectively in tumor cells, utilizing a heteroatom to react with an SO2 functional group and form a ring, ensuring targeted delivery and release of the active agent.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a cleavable linker system with triggering group is used, then selective release of active agent in tumor cells is achieved, but device complexity increases
Solution Approach 1:
The linker is divided into distinct functional segments: a triggering group (TG) that responds to tumor-specific conditions, a cleavable bond portion that connects the active agent, and a spacer moiety that provides structural separation. This segmentation allows each component to perform its specific function independently, enabling selective release while maintaining manageable structural complexity through modular design.
Solution Approach 2:
The triggering group acts as an intermediary that mediates between the stable conjugate structure in circulation and the active agent release at the target site. When the triggering group encounters tumor-specific conditions (such as enzymatic environments or pH levels), it activates the cleavable bond, thereby controlling the release of the active agent selectively in tumor cells without requiring complex external control mechanisms.
2Reliability
If targeting moiety is added to achieve tumor cell specificity, then therapeutic efficacy is improved, but manufacturing complexity increases
Solution Approach 1:
The conjugate design integrates multiple functions into a single molecular entity: the targeting moiety provides tumor cell recognition and binding, the linker provides stable attachment during circulation and controlled release at the target, and the active agent provides therapeutic effect. This multi-functionality in a single conjugate structure improves therapeutic efficacy through targeted delivery while avoiding the need for separate administration steps, thereby simplifying the overall treatment protocol despite the complexity of the manufacturing process.
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 described conjugates enable selective targeting and release of active agents in tumor cells, enhancing therapeutic efficacy while minimizing harm to healthy cells, and are applicable for treating conditions such as cancer, rheumatoid arthritis, and immune disorders.
Implementation Method 1
TG is a triggering group that, when activated, generates an N, O, or S atom capable of reacting with the SO2 to displace (Q)q-(L′)w and form a 5- or 6-membered ring including X—SO2 and the intervening atoms of Ar
Data Source
AI summary
Provided are a compound including a cleavable linker, a use thereof, and an intermediate compound for preparing the same, and more particularly, the compound including a cleavable linker of the present invention may include an active agent (for example, a drug, a toxin, a ligand, a probe for detection, etc.) having a specific function or activity, a SO2 functional group which is capable of selectively releasing the active agent, and a functional group which triggers a chemical reaction, a physicochemical reaction and/or a biological reaction by external stimulation, and may further include a ligand (for example, oligopeptide, polypeptide, antibody, etc.) having binding specificity for a desired target receptor.