Novel Linker Compound for Antibody-Drug Conjugates
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Solution Overview
Problem
Current linker compounds for antibody-drug conjugates lack excellent plasma stability and chemical stability, and they often release the drug non-selectively, leading to toxic side effects.
Innovation Solution
A novel linker compound represented by Formula 1 and its corresponding ligand-drug conjugate, which features a self-eliminating linker and a triggering group capable of initiating a 1,6-elimination reaction for selective drug release within target cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a thiol-maleimide linker is used as a non-cleavable linker, then the antibody-drug conjugate can be formed, but the chemical and plasma stability is low and potency is reduced
Solution Approach 1:
The patent changes the chemical parameters of the linker by using a disulfide bond instead of a thiol-maleimide bond, and introducing a self-immolative group with specific chemical properties that provide both plasma stability and controlled release capability through parameter optimization
Solution Approach 2:
The patent creates a composite linker structure combining a disulfide bond, a self-immolative group (such as a p-aminobenzyl alcohol derivative), and a triggering group, which together provide both stability in plasma and selective release at the target site
2Productivity
If a chemically separable linker (disulfide, hydrazone, or oxime bond) is used, then the drug can be separated from the antibody, but the drug may dissociate at locations unrelated to the target site resulting in toxic side effects
Solution Approach 1:
The patent introduces a self-immolative group as an intermediary between the disulfide bond and the drug. This intermediary remains intact during circulation, prevents premature drug release, and only triggers drug release after the disulfide bond is cleaved by intracellular glutathione, thus eliminating toxic side effects
Solution Approach 2:
The patent designs the linker so that the disulfide bond is cleaved first by intracellular glutathione, which then triggers the subsequent decomposition of the self-immolative group and release of the drug. This preliminary action ensures the drug is only released after entering the target cell
3Object-generated harmful factors
If a linker with self-immolative group is used for enzymatic hydrolysis, then selective drug release can be achieved, but plasma stability and chemical stability are not excellent
Solution Approach 1:
The patent optimizes the chemical parameters by using a disulfide bond instead of hydrolyzable bonds like hydrazone or oxime, and carefully designing the self-immolative group to be stable at physiological pH and plasma conditions but decomposable under intracellular conditions through parameter optimization
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 novel linker compound achieves excellent plasma and chemical stability, enabling rapid and selective release of the drug within target cells, thereby minimizing systemic toxicity and maximizing therapeutic efficacy.
Implementation Method 1
a triggering group (T) capable of initiating a 1,6-elimination reaction for selective drug release within target cells
Implementation Method 2
When the compound of Formula 1 comprises a beta-galactoside triggering group, the compound can be dissociated by an enzyme such as beta-galactosidase
Implementation Method 3
the compound can be dissociated by an enzyme such as beta-galactosidase
Data Source
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AI summary
The present invention provides a novel linker compound and a ligand-drug conjugate thereof. This can stably deliver an active ingredient to a target site and rapidly release the active ingredient at the target site, and thus can increase efficacy of the active ingredient and can prevent the active ingredient from causing side effects at locations other than the target location.