Stable Linker-Payload Compound for ADC Linkage Stability
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Solution Overview
Problem
Existing antibody-drug conjugates (ADCs) using thiosuccinimide linkages for connecting cytotoxic payloads with targeting antibodies are unstable under physiological conditions, leading to premature release of cytotoxins and enhanced off-target toxicity, limiting their clinical application.
Innovation Solution
Development of a stable linker-payload compound with a ring-opened succinimide structure that prevents reverse Michael addition and thiol exchange, ensuring prolonged half-life and targeted delivery of Eribulin in ADCs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If thiosuccinimide linkage is used to conjugate small molecule drug with targeting antibody, then conjugation efficiency is improved, but linkage stability deteriorates leading to premature payload release
Solution Approach 1:
The patent changes the chemical structure parameter of the linkage from thiosuccinimide to a stable non-thiol based structure (such as succinimide or other heterocyclic rings), eliminating the reverse Michael addition and thiol exchange reactions while maintaining conjugation efficiency through alternative chemistry
Solution Approach 2:
The patent employs a disposable stable linkage structure that prevents premature release throughout circulation, ensuring the payload remains bound until reaching the target site, thus eliminating the need for repeated dosing due to premature release
2Device complexity
If thiosuccinimide linkage is used for ADC preparation, then conjugation process is simplified, but off-target toxicity increases due to premature cytotoxin release
Solution Approach 1:
The patent modifies the chemical parameters of the linkage to eliminate thiol-based chemistry, using alternative stable linkages that prevent cytotoxin release in circulation, thereby reducing off-target toxicity while maintaining process simplicity
Solution Approach 2:
The patent converts the potential harm of premature release into benefit by designing a linkage that specifically prevents release in circulation but allows controlled release at the target site through enzymatic cleavage or other trigger mechanisms, thus transforming the stability issue into a targeted delivery advantage
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 stable linker-payload compound enhances the safety and efficacy of ADCs by reducing premature payload release, increasing systemic circulation time, and improving accumulation at target sites, thus providing a safer and more effective treatment for cancers.
Implementation Method 1
L′ is Cleavable sequence 1 comprising an amino acid sequence which can be cleaved by enzyme
Implementation Method 2
The thiosuccinimide linkage is unstable due to potential reverse Michael addition or thio-exchanging under physiological condition
Data Source
AI summary
A linker-payload compound for targeting molecule-drug conjugate, and the corresponding conjugate, the preparation and use thereof are provided.