Cleavable Linker Conjugates Using Cyclization for Selective Payload Release
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Solution Overview
Problem
Existing antibody-drug conjugates (ADCs) lack effective linkers that provide target-specificity with high activity in tumor cells and low activity in healthy cells, necessitating improved linker components for developing targeted anti-cancer agents.
Innovation Solution
Conjugates comprising a cleavable linker system with a targeting moiety (CB) and a spacer moiety (L') connected via a —S(═O)(═N—)— group, where a triggering group (TG) activates to form a 5-6-membered ring, releasing the active agent selectively in target cells, using heteroatoms like N, O, or S for intramolecular cyclization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a cleavable linker system with triggering group is used, then target-specificity and selective release in tumor cells is improved, but device complexity and linker structure complexity increases
Solution Approach 1:
The linker is divided into distinct functional segments: a triggering group (TG) that responds to tumor-specific conditions, a spacer moiety (L') that provides structural separation, and a leaving group that enables active agent release. This segmentation allows each component to perform its specific function independently, achieving reliable target-specificity while managing complexity through modular design.
Solution Approach 2:
The triggering group is pre-configured with latent reactive groups that are activated only upon encountering tumor-specific conditions (such as specific enzymes or pH levels). This preliminary action ensures that the linker remains stable during circulation but automatically activates at the target site, improving reliability without requiring complex external control mechanisms.
2Reliability
If a cleavable linker with intramolecular cyclization mechanism is used, then selective release of active agent in target cells is improved, but manufacturing complexity increases
Solution Approach 1:
The linker employs self-service through intramolecular cyclization, where the triggering group automatically reacts with the spacer moiety upon activation to form a cyclic structure. This self-contained mechanism eliminates the need for external catalysts or complex manufacturing processes, achieving selective release while simplifying manufacturing by relying on the molecule's own structural features.
Solution Approach 2:
The reactive groups necessary for cyclization are merged into the linker structure itself, combining the triggering function, spacing function, and release mechanism into a single integrated molecular system. This merging reduces manufacturing complexity by eliminating the need for separate components or assembly steps.
3Productivity
If spacer moiety with heteroatom is used for intramolecular cyclization, then cleavage efficiency and active agent release is improved, but device complexity increases
Solution Approach 1:
The spacer moiety incorporates heteroatoms (such as oxygen, nitrogen, or sulfur) that change the chemical parameters of the linker, enabling intramolecular cyclization through nucleophilic attack. This parameter change (introduction of heteroatoms with specific electronic properties) dramatically improves cleavage efficiency by facilitating the cyclization reaction, while the complexity increase is offset by the predictable chemistry of common heteroatoms.
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 conjugates achieve targeted delivery and release of active agents in tumor cells, minimizing harm to healthy cells, and are applicable for treating conditions like cancer, rheumatoid arthritis, and immune deficiencies.
Implementation Method 1
a triggering group (TG) activates to form a 5-6-membered ring, releasing the active agent selectively in target cells, using heteroatoms like N, O, or S for intramolecular cyclization
Implementation Method 2
TG is a triggering group that, when activated, generates an N, O, or S atom capable of reacting with the —S(═O)(═N—)— to displace (Q)q-(L′)w and form a 5-6-membered ring
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 —S(═O)(═N—)— 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.