Sulfomaleimide Linker Stability in Antibody-Drug Conjugates
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Solution Overview
Problem
Current antibody-drug conjugates (ADCs) face issues with stability and efficacy due to the reversible nature of thiosuccinimide linkages, leading to drug loss and reduced antitumor activity, along with increased toxicity from non-targeted drug release.
Innovation Solution
A sulfomaleimide-based linker is developed to covalently attach drugs to antibodies, enhancing stability and efficiency by preventing drug loss and ensuring targeted delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If thiosuccinimide linkage is used to conjugate drug to antibody, then rapid and quantitative conjugation is achieved, but stability is reduced due to reversible reaction leading to drug loss
Solution Approach 1:
The patent changes the chemical parameters of the linker from thiosuccinimide to sulfomaleimide, specifically modifying the sulfur atom to a sulfone group (SO2). This parameter change transforms the reversible thiosuccinimide linkage into an irreversible sulfomaleimide linkage, maintaining rapid conjugation kinetics while eliminating the retro-Michael reaction that causes drug loss during circulation.
Solution Approach 2:
The patent creates a composite linker structure combining the maleimide reactive group with a sulfone moiety. This composite structure integrates the rapid reaction capability of maleimide with the enhanced stability of the sulfone group, resulting in a linker that achieves both high conjugation efficiency and exceptional stability in physiological conditions.
2Ease of manufacture
If thiosuccinimide linkage is used, then conjugation is quantitative without large excess of reagents, but harmful factors increase due to non-targeted drug release and toxicity
Solution Approach 1:
By changing the chemical composition of the linker from thiosuccinimide to sulfomaleimide, the patent eliminates the reversibility issue while maintaining the simplicity of the conjugation process. The sulfomaleimide linkage remains highly reactive toward thiols under physiological conditions, allowing quantitative conjugation without reagent excess, while the irreversible nature prevents non-targeted drug release and associated toxicity.
3Duration of action of stationary object
If prolonged circulation is allowed, then drug delivery to target is extended, but drug loss increases due to maleimide elimination via retro-Michael reaction
Solution Approach 1:
The patent modifies the chemical stability parameter of the linker by introducing the sulfone group, which creates an irreversible bond with thiols. This parameter change ensures that even during prolonged circulation times, the drug-antibody conjugate remains stable without undergoing retro-Michael reaction, thereby preventing drug loss while maintaining extended circulation for sustained target delivery.
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 sulfomaleimide linker improves the stability and efficacy of ADCs by maintaining drug attachment and ensuring targeted delivery to cancer cells, reducing toxicity and enhancing antitumor activity.
Implementation Method 1
the reaction of maleimides and thiols is very rapid under physiological conditions and is quantitative (without a large excess of both original species). However, thiosuccinimide formation is slowly reversible under physiological conditions.
Data Source
AI summary
The present invention relates to a linker of the following formula (I) or a salt thereof:The present invention relates to a linker-drug conjugate of the following formula (II) or a salt thereof:The present invention relates also to a binding unit-drug conjugate, such as an antibody-drug conjugate, of the following formula (III) or (IV) or a salt thereof:as well as a pharmaceutical composition comprising such a binding unit-drug conjugate and its use in the treatment of cancer.