HER2 Antibody-Drug Conjugate Linker for Stable DAR Control
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Solution Overview
Problem
Existing antibody-drug conjugates (ADCs) face issues with aggregation, reduced stability, and suboptimal therapeutic effects due to high drug-antibody ratios (DAR), leading to increased toxicity and side effects.
Innovation Solution
The introduction of a novel linker structure in the antibody-drug conjugate, covalently linking drug-linker assembly units to thiols generated by reducing interchain disulfide bonds in the antibody, maintains appropriate DAR and improves plasma stability and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the drug-antibody ratio (DAR) of ADCs is increased to increase the number of drugs entering the cell, then the intracellular drug concentration is improved, but the ADC molecules undergo severe aggregation and reduced stability, resulting in increased small-molecule toxins in the blood and causing toxic and side effects
Solution Approach 1:
The patent optimizes the drug-antibody ratio (DAR) parameter to a specific range (2-8) to balance intracellular drug concentration with ADC stability. By controlling this critical parameter, the invention achieves sufficient drug delivery while preventing aggregation and maintaining plasma stability, thereby resolving the contradiction between quantity and stability.
2Quantity of substance
If the drug-antibody ratio (DAR) of ADCs is increased to increase the number of drugs entering the cell, then the intracellular drug concentration is improved, but toxic and side effects are increased
Solution Approach 1:
The patent controls the DAR parameter within the range of 2-8 to optimize the balance between therapeutic efficacy and safety. This parameter optimization ensures sufficient intracellular drug concentration for tumor killing while preventing excessive small-molecule toxin release into the blood, thereby reducing toxic and side effects.
3Ease of operation
If existing ADC structures are used, then the basic targeting function is achieved, but the aggregation phenomenon occurs and plasma stability is reduced
Solution Approach 1:
The patent employs a composite structure consisting of antibody, optimized linker, and drug components with specific molecular weight and composition ratios. This composite design enhances plasma stability and reduces aggregation while maintaining the targeting function, resolving the contradiction between ease of operation and stability.
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 novel linker structure reduces aggregation, maintains consistent DAR, enhances plasma stability, and improves therapeutic effects, making the ADC more effective against tumors with reduced immunogenicity and side effects.
Implementation Method 1
covalently linking drug-linker assembly units to thiols generated by reducing interchain disulfide bonds in the antibody
Implementation Method 2
reducing interchain disulfide bonds in the antibody
Implementation Method 3
The introduction of a novel linker structure in the antibody-drug conjugate, covalently linking drug-linker assembly units to thiols generated by reducing interchain disulfide bonds in the antibody, maintains appropriate DAR and improves plasma stability and efficacy
Data Source
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AI summary
The present disclosure provides an antibody-drug conjugate, a preparation method, and use thereof, belonging to the field of medicine. The structure of the antibody-drug conjugate is shown in Formula I, in which the antibody Ab is an anti-HER2 antibody, q is an integer from 1 to 20, and D is a drug. The antibody-drug conjugate provided by the present disclosure has low aggregation and low naked antibody, appropriate DAR, exhibits excellent plasma stability and anti-tumor effect, can effectively inhibit tumor recurrence, and has good clinical application prospect.