Antibody-Drug Conjugate Thioether Linker Stability
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Solution Overview
Problem
Current antibody-drug conjugates (ADCs) face challenges with linker stability, bioactive molecule detachment due to enzyme hydrolysis, and increased toxicity, particularly with eribulin-based ADCs, which require improved reactive groups for enhanced targeting and reduced off-target effects.
Innovation Solution
A novel connector structure is introduced, comprising a peptide residue and a thioether linkage, allowing for a high drug loading capacity, faster onset, longer drug half-life, and improved stability, biocompatibility, and safety, while maintaining effective anti-tumor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional linkers are used to conjugate antibodies to small molecule toxins, then the ADC can be formed, but the linker is prone to hydrolysis causing bioactive molecules to detach before reaching target cells, resulting in loss of targeting and increased toxicity
Solution Approach 1:
The patent changes the chemical parameters of the linker by introducing a novel structure containing a peptide residue (L1) and a thioether linkage (L2), replacing conventional linkers. This parameter change in linker composition provides resistance to enzyme hydrolysis while maintaining stability, preventing premature detachment of bioactive molecules and reducing off-target toxicity.
2Reliability
If conventional linking sites on antibodies are used for conjugation, then the ADC can be constructed, but the bioactive molecules may fall off before reaching target cells due to enzyme action, causing loss of targeting
Solution Approach 1:
The patent introduces a novel connector structure as an intermediary between the antibody and the small molecule toxin. This connector contains a peptide residue and thioether linkage that act as a stable mediator, resisting enzyme hydrolysis and preventing premature release of the bioactive molecule, thereby maintaining targeting efficiency and reducing off-target effects.
3Productivity
If eribulin-based ADCs are developed, then potent anti-tumor activity can be achieved, but the toxicity is significantly increased requiring improved reactive groups for enhanced targeting
Solution Approach 1:
The patent applies local quality improvement by designing a specialized connector structure with specific local chemical properties (peptide residue L1 and thioether linkage L2) that enhances stability at the antibody-drug interface. This localized structural optimization prevents premature drug release specifically at off-target sites while maintaining the potent anti-tumor activity of eribulin at the target site.
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 ADC design achieves enhanced stability, reduced immunogenicity, and improved safety with effective anti-tumor performance, overcoming previous ADC limitations.
Implementation Method 1
A novel connector structure is introduced, comprising a peptide residue and a thioether linkage
Implementation Method 2
allowing for a high drug loading capacity, faster onset, longer drug half-life, and improved stability
Data Source
AI summary
Provided is an antibody-drug conjugate based on a microtubule inhibitor. Specifically provided are a compound as represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate of the compound, the pharmaceutically acceptable salt thereof or the stereoisomer thereof. The present invention further relates to an antibody-drug conjugate formed by means of connecting a targeting moiety with the compound as represented by formula (I), the pharmaceutically acceptable salt thereof, the stereoisomer thereof, or the solvate of the compound, the pharmaceutically acceptable salt thereof or the stereoisomer thereof via a thioether bond.MC—L1—L2—D (I)