Thiol-Selective Linker Composition for Stable ADC Drug Loading
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Solution Overview
Problem
Existing antibody-drug conjugates (ADCs) suffer from instability and low selectivity due to maleimide-based linkers, leading to reduced efficacy and potential toxic reactions.
Innovation Solution
A novel linker that selectively conjugates with thiols in biomacromolecules, maintaining a stable drug-to-antibody ratio (DAR) under physiological conditions, enhancing the therapeutic index of ADCs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If maleimide-based linkers are used in ADCs, then conjugation with antibody cysteine can be achieved, but the ADC undergoes retro-Michael addition during systemic circulation causing instability and toxic reactions
Solution Approach 1:
The patent modifies the chemical structure of the maleimide linker by introducing electron-withdrawing groups (such as fluorine atoms or cyano groups) at specific positions on the maleimide ring. This structural parameter change increases the electrophilicity of the maleimide double bond, enhancing its reactivity toward thiol groups while simultaneously stabilizing the resulting succinimide ring against retro-Michael addition, thus resolving the contradiction between conjugation efficiency and ADC stability
Solution Approach 2:
The patent creates a composite linker structure that combines maleimide with additional functional groups or structural elements (such as heterocyclic rings or rigid scaffolds). This composite design maintains the desirable thiol-reactivity of maleimide while the additional components provide steric protection or electronic stabilization that prevents retro-Michael addition and off-target reactions, thereby improving both conjugation efficiency and circulation stability
2Ease of manufacture
If maleimide-based linkers are used in ADCs, then conjugation can proceed, but the maleimide reacts with thiol-containing proteins or small molecules causing toxic reactions
Solution Approach 1:
By modifying the electronic and steric parameters of the maleimide linker through substituent introduction, the patent creates a more selective reactive species that preferentially reacts with the intended antibody cysteine targets while having reduced reactivity toward off-target thiol-containing proteins and small molecules, thus maintaining conjugation capability while reducing toxic reactions
Solution Approach 2:
The modified maleimide linker acts as a more selective intermediary that facilitates the desired conjugation between antibody and payload while its altered structure prevents unwanted interactions with plasma proteins and other biomolecules, effectively mediating the conjugation process with higher selectivity and lower toxicity
3Ease of manufacture
If traditional linkers are used, then ADC can be prepared, but the drug-to-antibody ratio (DAR) changes after incubation indicating instability
Solution Approach 1:
The patent optimizes the chemical parameters of the linker (such as electrophilicity, steric bulk, and ring strain) to create a conjugation bond that is both kinetically favorable for formation and thermodynamically stable under physiological conditions, ensuring that the DAR remains constant during circulation and storage, thus improving reliability while maintaining ease of preparation
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 new linker provides high conjugation efficiency and chemical stability, ensuring ADCs maintain their effectiveness over time and reducing toxic side effects.
Implementation Method 1
antibody conjugation is generally achieved by reducing the interchain cysteine disulfide bonds of the antibody to provide multiple free thiols as conjugation sites, followed by a Michael addition reaction with maleimide
Implementation Method 2
ADCs obtained via thiol-Michael addition may undergo retro-Michael addition during systemic circulation, and the resulting maleimide can further undergo Michael addition reactions with various thiol-containing proteins or small molecules
Data Source
AI summary
A linker and a use thereof in a ligand drug conjugate. Provided is a compound as represented by formula (III), or a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutically acceptable salt of a solvate thereof. The linker can be selectively coupled with thiols in biomacromolecules, has extremely high coupling efficiency and high drug loading capacity; and also shows high chemical stability.