Self-Stabilizing Linkers Prevent Maleimide Transfer in ADCs
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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 in the presence of excess cysteine or glutathione, which compromises the stability and efficacy of the conjugate.
Innovation Solution
Development of self-stabilizing linkers that incorporate a basic group and an electron-withdrawing group to catalyze the hydrolysis of the succinimide ring, ensuring stability in circulation while allowing for rapid release within tumor cells, thereby preventing unwanted maleimide transfer and maintaining drug loading.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If electrophilic maleimide functional groups are used to conjugate with thiol groups in ADCs, then the conjugation reaction proceeds with high specificity and fast kinetics under gentle conditions, but the thio-substituted product undergoes slow elimination reversing the reaction, leading to maleimide transfer to other thiols in plasma
Solution Approach 1:
The patent introduces a stabilizing group as an intermediary element that mediates between the maleimide-thiol conjugation and prevents the reverse elimination reaction. This stabilizing group acts as a protective intermediary that blocks the elimination pathway while maintaining the conjugation stability.
Solution Approach 2:
The patent modifies the chemical parameters of the maleimide linker by incorporating stabilizing groups with specific electronic properties (electron-withdrawing or electron-donating) to change the reactivity parameters of the succinimide ring, thereby preventing elimination and stabilizing the conjugate in circulation.
2Quantity of substance
If the maleimide-thiol conjugation is allowed to proceed to completion, then high drug loading is achieved, but the conjugate becomes unstable in plasma and transfers maleimide to serum albumin or other thiols
Solution Approach 1:
The stabilizing group serves as an intermediary protective element that prevents direct interaction between the maleimide moiety and plasma thiols, thereby blocking the harmful transfer reaction while allowing high drug loading to be achieved.
Solution Approach 2:
The patent applies preliminary anti-action by incorporating the stabilizing group into the linker structure before conjugation, which pre-empts and prevents the harmful elimination and maleimide transfer reactions that would otherwise occur in plasma.
3Reliability
If standard maleimide linkers are used to achieve stable conjugation, then the ADC maintains integrity in circulation, but the linker cannot rapidly release the drug within tumor cells
Solution Approach 1:
The patent applies local quality by creating different functional regions within the linker: one region (the stabilizing group) provides circulation stability by preventing elimination, while another region (the cleavable portion) provides rapid drug release in tumor cells through enzyme-sensitive or pH-sensitive bond cleavage.
Solution Approach 2:
The linker is segmented into distinct functional modules: a stabilizing group module that prevents elimination in circulation, a cleavable bond module that enables rapid release in tumor cells, and a drug payload module. This segmentation allows each module to perform its specific function independently.
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 enhance the stability of ADCs in circulation, preventing drug loss and maintaining therapeutic efficacy by ensuring that the conjugate remains intact until it reaches the tumor cells, where it can effectively induce cell death.
Implementation Method 1
incorporate a basic group and an electron-withdrawing group to catalyze the hydrolysis of the succinimide ring
Implementation Method 2
a base and an electron-withdrawing group are positioned to catalyze the hydrolysis of the succinimide ring
Data Source
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AI summary
The present invention provides Ligand-Drug Conjugates, Drug-Linkers, Linkers, and Ligand-Linker Conjugates comprising a self-stabilizing linker assembly component.