Thiol-Reactive ADC Linkers for Off-Target Toxicity Control
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Solution Overview
Problem
Existing antibody-drug conjugates (ADCs) face challenges with narrow therapeutic windows and unpredictable dose-limiting toxicities due to off-target effects, necessitating improved linker-payload chemistry for targeted delivery and reduced off-target toxicity.
Innovation Solution
Development of linkers containing thiol-reactive groups, such as substituted acrylic and propiolic groups, to conjugate cytotoxic agents with cell-binding molecules, allowing for multiple drug attachments and controlled drug ratios, enhancing targeted delivery and reducing off-target exposure.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional chemotherapeutic drugs are used, then they can treat malignant cells, but they cause narrow therapeutic windows due to inability to discriminate between normal and malignant cells
Solution Approach 1:
The patent introduces a cell-binding molecule as an intermediary carrier that specifically binds to malignant cells, transporting the cytotoxic agent only to the target cells. This mediator (cell-binding molecule) enables selective delivery, discriminating between normal and malignant cells, thereby expanding the therapeutic window and reducing off-target toxicity while maintaining cytotoxic efficacy.
Solution Approach 2:
The patent segments the chemotherapeutic system into three distinct components: (1) cell-binding molecule for target recognition, (2) linker for controlled drug release, and (3) cytotoxic agent for cell killing. This segmentation allows each component to perform its specific function independently, with the cell-binding molecule ensuring selective targeting and the linker ensuring controlled release only at the target site, thereby improving therapeutic window and reducing off-target effects.
2Reliability
If multiple cytotoxic agents are conjugated to cell-binding molecules, then efficacy is increased, but complexity of conjugation chemistry increases
Solution Approach 1:
The patent employs universal linker structures with standardized thiol-reactive groups that can conjugate multiple different cytotoxic agents to various cell-binding molecules. The linker serves multiple functions: providing stable circulation, enabling controlled release, and facilitating conjugation to multiple drugs. This universal approach allows multiple cytotoxic agents to be conjugated through the same linker platform, increasing efficacy while managing conjugation chemistry complexity through standardization.
Solution Approach 2:
The patent utilizes parameter changes in the linker design, specifically employing thiol-reactive groups that undergo controlled chemical transformation. The linker remains stable under circulation conditions but undergoes parameter change (bond cleavage) under specific intracellular conditions to release the cytotoxic agent. This parameter-based control mechanism enables multiple drugs to be conjugated with consistent chemistry while maintaining controlled release properties, thereby increasing efficacy without proportionally increasing conjugation complexity.
3Object-affected harmful factors
If stable linkers are used for circulation, then off-target toxicity is reduced, but drug release in target cells may be impaired
Solution Approach 1:
The patent employs dynamic linker design where the linker transitions from a stable state during circulation to an active release state upon cellular internalization. The thiol-reactive group in the linker maintains stability in the bloodstream but becomes dynamically active inside the target cell, where it reacts with intracellular thiols to release the cytotoxic agent. This dynamic behavior allows the linker to simultaneously reduce off-target toxicity during circulation and ensure efficient drug release at the target site.
Solution Approach 2:
The linker acts as a chemical intermediary that mediates between the stable circulation requirement and the drug release requirement. It contains a thiol-reactive group that serves as the release mechanism, remaining inert during circulation but becoming activated by intracellular thiols. This intermediary functionality allows the system to achieve both stable circulation (reducing off-target toxicity) and efficient intracellular drug release (maintaining reliability of drug release).
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 proposed linkers enable prolonged circulation half-life, increased efficacy through dual targeting strategies, and minimize off-target toxicity, resulting in improved batch-to-batch consistency and pharmacokinetic properties of ADCs.
Implementation Method 1
linkers having a group of propioloyl, substituted acryl (acryloyl), or disubstituted propanoyl, used for the conjugation of compounds, in particular, cytotoxic agents to a cell-binding molecule
Data Source
AI summary
The present invention relates to linkers having a group of propioloyl, substituted acryl (acryloyl), or disubstituted propanoyl, and using such linkers for the conjugation of compounds, in particular, cytotoxic agents to a cell-binding molecule.