Self-Stabilizing Linkers for Antibody-Drug Conjugates
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Solution Overview
Problem
Antibody-drug conjugates (ADCs) face stability issues due to the reversible reaction of electrophilic maleimide functional groups with thiols, leading to unintended transfer of the maleimide to other thiols in plasma or when incubated with excess cysteine or glutathione, resulting in loss of drug payload.
Innovation Solution
Development of self-stabilizing linkers that incorporate a basic group proximal to the maleimide, combined with an electron withdrawing group, to catalyze the hydrolysis of the succinimide ring, creating a stable bioconjugate that maintains drug loading and prevents transfer reactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If electrophilic maleimide functional group is used to react with thiol groups in ADC preparation, then high specificity and fast reaction kinetics are achieved, but the resulting thio-substituted product undergoes slow elimination and transfers maleimide to other thiols in plasma
Solution Approach 1:
The patent modifies the chemical structure of the maleimide linker by introducing electron-withdrawing groups (such as fluorine atoms or carbonyl groups) at specific positions on the maleimide ring. This structural parameter change alters the electronic properties of the maleimide, reducing its electrophilicity and thereby preventing reverse elimination reactions and thiol transfer, while maintaining forward reaction kinetics with antibody thiols.
Solution Approach 2:
The patent converts the harmful reversible nature of the maleimide-thiol reaction into a beneficial feature by designing linkers where the reverse reaction is suppressed through electronic effects. The electron-withdrawing groups stabilize the thio-substituted succinimide product by reducing the electrophilic character of the maleimide carbonyl carbons, thereby preventing elimination and transforming the potential instability into a stable, non-reversible conjugation.
2Reliability
If maleimide transfers to cysteine 34 of serum albumin in plasma, then the reversible reaction is detected, but drug payload is lost from the ADC
Solution Approach 1:
The patent introduces electron-withdrawing groups as chemical intermediaries that mediate between the maleimide reactive group and the thiol conjugation site. These groups act as electronic buffers that reduce the electrophilicity of the maleimide, thereby preventing the maleimide from reacting with plasma thiols such as cysteine 34 of serum albumin, while still allowing controlled reaction with antibody thiols during conjugation.
3Adaptability or versatility
If ADC is incubated with excess cysteine or glutathione, then maleimide transfer reaction occurs, but conjugate stability is compromised
Solution Approach 1:
The patent changes the electronic parameters of the maleimide linker through substitution with electron-withdrawing groups, which fundamentally alters the reaction equilibrium. This parameter change makes the conjugation essentially irreversible even in the presence of excess thiols like cysteine or glutathione, as the electron-deficient maleimide is stabilized and less prone to elimination and transfer reactions under physiological incubation conditions.
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 self-stabilizing linkers ensure the ADCs remain stable in circulation, maintaining drug loading and preventing drug transfer, while allowing for rapid hydrolysis within tumor cells, enhancing therapeutic efficacy.
Implementation Method 1
incorporate a basic group proximal to the maleimide, combined with an electron withdrawing group, to catalyze the hydrolysis of the succinimide ring
Implementation Method 2
catalyze the hydrolysis of the succinimide ring, creating a stable bioconjugate
Data Source
AI summary
The present invention provides Ligand-Drug Conjugates, Drug-Linkers, Linkers, and Ligand-Linker Conjugates comprising a self-stabilizing linker assembly component.