Dual-Linker Antibody-Drug Conjugates for Solubility and Drug Loading
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Solution Overview
Problem
Existing antibody drug conjugates face solubility issues due to the use of hydrophobic linkers, affecting biocompatibility and pharmaceutical efficacy, particularly when delivering multiple pharmaceutically active drugs.
Innovation Solution
The development of antibody-drug conjugates using dual linkers that covalently attach two pharmaceutically active drugs to a single antibody, incorporating hydrophilic moieties and enzyme cleavage elements to enhance solubility and delivery efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If hydrophobic linkers are used to attach drug moieties to antibodies, then the drug delivery capability is improved, but the solubility of the antibody-drug conjugate deteriorates
Solution Approach 1:
The patent divides the linker into two distinct segments: a hydrophobic portion that facilitates drug attachment and delivery, and a hydrophilic portion that maintains solubility. This segmentation allows each part to perform its specific function without compromising the overall conjugate performance, directly resolving the contradiction between drug delivery capability and solubility
Solution Approach 2:
The patent employs composite linker structures that combine hydrophobic and hydrophilic moieties in a single molecule. This composite approach enables the linker to simultaneously provide hydrophobic interactions for drug binding and hydrophilic characteristics for maintaining aqueous solubility, thus resolving the contradiction between these two opposing requirements
2Quantity of substance
If multiple hydrophobic drugs are attached to a single antibody, then the therapeutic efficacy is improved, but the biocompatibility deteriorates due to solubility issues
Solution Approach 1:
By segmenting the linker into hydrophobic and hydrophilic portions, the patent enables attachment of multiple hydrophobic drug moieties while the hydrophilic portions collectively maintain the overall solubility and biocompatibility of the conjugate, allowing higher drug loading without compromising biocompatibility
Solution Approach 2:
The patent changes the chemical parameters of the linker by incorporating hydrophilic groups with appropriate polarity and hydrogen-bonding capabilities. This parameter modification increases the hydrophilicity of the overall conjugate structure, enabling it to tolerate and remain soluble even when multiple hydrophobic drugs are attached, thus maintaining biocompatibility
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 dual linker system allows for the delivery of twice the number of drug molecules per antibody, improving solubility and pharmacokinetic properties, effectively targeting and treating cancer cells.
Implementation Method 1
antibody-drug conjugates using dual linkers that covalently attach two pharmaceutically active drugs to a single antibody
Implementation Method 2
incorporating hydrophilic moieties and enzyme cleavage elements to enhance solubility
Implementation Method 3
incorporating hydrophilic moieties and enzyme cleavage elements to enhance solubility and delivery efficiency
Data Source
AI summary
The present disclosure relates to antibody-drug conjugates (ADCs) comprising an antibody or an antigen-binding fragment thereof covalently linked to two pharmaceutically active drugs through a dual linker. Linker-drug conjugates comprising the dual linker and the pharmaceutically active drugs are also disclosed. Such linkers are a convenient way of delivering two (e.g. two different or two of the same) drugs connected to a single antibody. Such linkers may be particularly useful in improving the solubility of antibody drug conjugates (ADCs) which comprise one or more hydrophobic drug compounds.