Hydrolysable Maleimide Linkers for Antibody Drug Conjugates
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Solution Overview
Problem
Existing chemical inducers of degradation (CIDEs) face challenges with targeted delivery and stability, leading to fast metabolism, short half-life, and low bioavailability.
Innovation Solution
The use of hydrolysable maleimide-containing linkers to covalently bind CIDEs to antibodies, forming Ab-L1-CIDE conjugates, which enhances targeted delivery and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CIDEs are used as standalone molecules, then they can induce protein degradation, but they suffer from fast metabolism, short half-life, and low bioavailability
Solution Approach 1:
The patent combines the CIDE molecule with an antibody through a hydrolysable maleimide-containing linker to form an Ab-CIDE conjugate. This merging of the small molecule CIDE with the large antibody molecule protects the CIDE from rapid metabolism and clearance, thereby extending its half-life and improving its stability in vivo.
Solution Approach 2:
The patent creates a composite molecular structure consisting of three components: an antibody, a hydrolysable maleimide-containing linker, and a CIDE molecule. This composite Ab-L1-CIDE conjugate leverages the stability and long circulation half-life of the antibody while retaining the protein degradation function of the CIDE, thereby resolving the contradiction between stability and duration of action.
2Reliability
If CIDEs are used as standalone molecules, then they can induce protein degradation, but they exhibit low bioavailability
Solution Approach 1:
By merging the CIDE with an antibody to form an Ab-CIDE conjugate, the patent exploits the antibody's ability to navigate biological barriers and achieve high local concentrations at target sites. This significantly improves the bioavailability of the CIDE, allowing effective concentrations to be achieved in tissues that would be difficult to reach with standalone small molecules.
3Reliability
If CIDEs are used as standalone molecules, then they can induce protein degradation, but they lack targeted delivery capability
Solution Approach 1:
The patent merges the CIDE molecule with an antibody, which provides inherent targeted delivery capability through antigen-antibody recognition. The antibody component directs the conjugate to specific cells or tissues expressing the target antigen, thereby conferring targeted delivery to the CIDE without requiring additional complex delivery systems.
Solution Approach 2:
The hydrolysable maleimide-containing linker serves as an intermediary component that covalently connects the CIDE to the antibody. This linker enables the formation of the Ab-CIDE conjugate while maintaining the functional integrity of both the antibody's targeting capability and the CIDE's degradation function, thereby achieving targeted delivery without excessive complexity.
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 Ab-L1-CIDE conjugates achieve improved targeted delivery and increased stability, leading to enhanced therapeutic efficacy and a broader therapeutic window.
Implementation Method 1
hydrolysable maleimide-containing linkers that are able to bind covalently in a stable manner to provide increased number of bound linkers to the antibody
Implementation Method 2
hydrolysable maleimide-containing linkers
Data Source
AI summary
The subject matter described herein relates generally to hydrolysable maleimide-containing molecules that are useful as linkers to covalently bind chemical inducers of degradation to antibodies and to the conjugates produced therefrom and their uses to treat conditions, and to the uses of the conjugates in treating diseases and conditions where targeted protein degradation is beneficial.