Amide Surrogate Linkers for ADC Stability
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Solution Overview
Problem
Current antibody-drug conjugates (ADCs) face challenges in maintaining stability during circulation while ensuring rapid release of cytotoxic compounds at target sites, with premature cleavage of amide bonds leading to undesirable side effects.
Innovation Solution
A linker with an amide surrogate unit is introduced to replace the N-terminal amide bond, enhancing the stability of ADCs in circulation and facilitating controlled release of cytotoxic drugs at target cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If an amide bond is used in the linker to enable lysosomal enzymatic cleavage for drug release, then the drug can be released at the target site, but the linker may undergo premature cleavage in circulation leading to systemic side effects
Solution Approach 1:
The patent changes the chemical parameter of the linker by replacing the amide bond with a chemically distinct amide surrogate bond that has different stability characteristics. This parameter change allows the linker to maintain stability in circulation while still enabling controlled drug release at the target site through alternative mechanisms
Solution Approach 2:
The amide surrogate acts as an intermediary component that replaces the traditional amide bond. It serves as a mediator that prevents premature cleavage by lysosomal enzymes in circulation while still allowing for controlled drug release at the target site, thus resolving the contradiction between stability and controlled release
2Object-generated harmful factors
If the linker is made highly stable to prevent premature cleavage, then systemic side effects are reduced, but the ability to rapidly release drug at the target site may be compromised
Solution Approach 1:
The patent modifies the chemical parameters of the linker to create an amide surrogate with enhanced stability that prevents premature cleavage. This parameter change is designed to maintain the ability for rapid drug release at the target site while reducing systemic side effects from premature release during circulation
3Productivity
If a lysosomal enzymatic cleavable peptide component is used in the linker, then drug release at target cells is enabled, but other amide bonds may undergo premature cleavage leading to undesirable side effects
Solution Approach 1:
The amide surrogate serves as an intermediary that replaces vulnerable amide bonds in the linker. It prevents premature cleavage by lysosomal enzymes while maintaining the peptide component's ability to enable drug release at target cells through controlled enzymatic cleavage
Solution Approach 2:
The patent changes the chemical structure of the linker by substituting the amide bond with an amide surrogate, altering the cleavage resistance parameter. This allows the peptide component to maintain its drug release function while the surrogate prevents premature cleavage and associated side effects
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 modified linker improves the stability and efficacy of ADCs by minimizing systemic side effects and ensuring targeted drug delivery, while maintaining the ability to release cytotoxic compounds at the intended site.
Implementation Method 1
The C-terminal amide bond in this part of the linker that can be easily cleaved at target cells by lysosomal enzymes is essential to the drug releasing mechanism. Other amide bonds on the linker if undergo prematurely cleavage may lead to undesirable side effects
Implementation Method 2
The C-terminal amide bond in this part of the linker that can be easily cleaved at target cells by lysosomal enzymes is essential to the drug releasing mechanism
Data Source
AI summary
The present invention relates to linkers, containing amide surrogates with a regular or a novel lysosomal enzymatic cleavable dipeptidic unit, to connect cytotoxic drugs to antibodies. The present invention also relates to ADCs (antibody-drug conjugates) derived from these amide surrogate linkers for the treatment of cancers.