Acidic ADC Linker Design for High Drug Load Plasma Stability
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Solution Overview
Problem
Existing antibody-drug conjugates face issues with drug stability in plasma due to sulfhydryl exchange, leading to reduced efficacy and increased toxicity, and higher drug loads result in unstable pharmacokinetics and aggregation.
Innovation Solution
Incorporation of an acidic stabilization junction in the antibody-drug conjugate, which includes an acidic amino acid or oligopeptide unit, reduces succinimide and antibody conjugate sulfhydryl exchange, maintaining stability and improving hydrophilicity, allowing for higher drug loads without compromising pharmacokinetic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If maleimide linker is used to couple antibody to drug via sulfhydryl groups, then conjugation efficiency and selectivity are improved, but drug stability in plasma deteriorates due to reversible sulfhydryl exchange
Solution Approach 1:
The patent introduces a basic group (such as dimethylamine or diethylamine) adjacent to the succinimide ring in the maleimide linker. This chemical modification changes the local pH environment and electronic properties, which suppresses the reverse Michael addition reaction between the succinimide ring-opened product and albumin sulfhydryl groups in plasma, thereby preventing drug shedding while maintaining conjugation efficiency
Solution Approach 2:
The patent creates a composite linker structure that combines the maleimide sulfhydryl-reactive group with a basic amino group in close proximity. This composite structure leverages the reactivity of maleimide for efficient conjugation while the basic group provides plasma stability by electrostatic repulsion and pH buffering, achieving both high conjugation efficiency and drug stability
2Quantity of substance
If drug load is increased to improve therapeutic efficacy, then treatment effectiveness is improved, but pharmacokinetic stability deteriorates due to aggregation and instability
Solution Approach 1:
The basic group modification changes the surface charge and hydrophilicity parameters of the ADC molecule. This parameter change reduces intermolecular hydrophobic interactions and electrostatic aggregation, enabling higher drug loads (DAR 4-8) to be maintained in solution without precipitation or aggregation, thus preserving pharmacokinetic stability at high drug loads
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 acidic stabilization junction enhances plasma stability and pharmacokinetics, enabling higher drug loads with improved efficacy and reduced aggregation, maintaining similar or better activity compared to lower drug loads.
Implementation Method 1
it has been reported that the cyclic thioether addition product formed by maleimide and sulfhydryl can undergo hydrolysis in an aqueous environment to form a thioether ring-opened product
Implementation Method 2
the cyclic thioether addition product formed by maleimide and sulfhydryl can undergo hydrolysis in an aqueous environment to form a thioether ring-opened product
Data Source
AI summary
The present invention provides a special drug conjugate having a hydrophilic acidic stabilization junction. Compared with a conjugate having a lower drug loading, due to the introduction of the acidic stabilization junction, the conjugate in the present invention can also have a higher drug loading (that is, each targeted reagent has more hydrophilic drug junctions), keeps a desired PK property and has a same or better activity in a body.