Dual-Cleavage Ester-Glycoside Linkers for ADC Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current antibody-drug conjugates (ADCs) face challenges in using carboxylic ester linkers for hydroxy-containing payloads, as they are susceptible to plasma hydrolases and lack stability in circulation, while requiring cleavage upon internalization for drug release.
Innovation Solution
The development of dual-cleavage ester-glycoside linkers, where a monosaccaride moiety provides steric hindrance in plasma, preventing extracellular cleavage, and is later removed by lysosomal glycosidases, allowing intracellular ester hydrolysis for payload release.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a carboxylic ester linker is used to connect the antibody to the hydroxy-containing payload, then the payload can be delivered to the target cell, but the linker is susceptible to plasma hydrolases and lacks stability in circulation
Solution Approach 1:
The linker is segmented into two distinct cleavage sites: a plasma-stable ester bond and a lysosomal glycosidic bond. The monosaccharide moiety acts as a protective segment in circulation, while serving as a removable segment inside the cell, enabling differential stability in different biological environments.
Solution Approach 2:
The linker exhibits different chemical properties at different locations: the ester bond provides plasma stability, while the glycosidic bond provides intracellular cleavability. The monosaccharide moiety provides steric hindrance in plasma but is recognized and removed by lysosomal glycosidases, creating location-specific reactivity.
2Duration of action of stationary object
If the linker is designed to be stable in plasma, then circulation time is extended, but the drug release efficiency upon internalization is reduced
Solution Approach 1:
The monosaccharide moiety acts as an intermediary protective group that prevents premature cleavage in plasma but is specifically removed by lysosomal glycosidases after internalization. This intermediary element enables the linker to maintain stability during circulation while ensuring efficient drug release in the intracellular environment.
Solution Approach 2:
The linker's chemical environment changes from the reducing environment of plasma to the acidic, enzyme-rich environment of lysosomes. The dual-cleavage design exploits these parameter changes, with the ester bond stable in plasma but cleavable in lysosomes, and the glycosidic bond serving as a removable protective group in the intracellular environment.
3Ease of manufacture
If a simple ester linker is used, then the synthesis is straightforward, but the linker lacks stability against plasma hydrolases
Solution Approach 1:
The linker is a composite structure combining a carboxylic ester moiety with a monosaccharide unit. This composite design provides both the desired plasma stability (through the glycosidic bond and steric hindrance) and the required intracellular cleavability (through lysosomal glycosidase recognition), while remaining synthetically accessible through established conjugation chemistry.
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
This design enhances plasma stability and efficient drug release within cells, maintaining ADC stability in circulation while ensuring payload activation upon internalization.
Implementation Method 1
a monosaccaride moiety provides steric hindrance in plasma, preventing extracellular cleavage
Implementation Method 2
is later removed by lysosomal glycosidases, allowing intracellular ester hydrolysis for payload release
Data Source
AI summary
The present disclosure provides antibody-drug conjugate structures, where the antibody-drug conjugate includes a cleavable linker containing an ester group that links the antibody to the drug. The disclosure also encompasses compounds and methods for production of such conjugates. In addition, the disclosure also encompasses pharmaceutical compositions and methods of using the conjugates.