Heterocyclic Linker for Antibody Drug Conjugate Stability
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Solution Overview
Problem
There is a need for alternative and improved linkers in protein drug conjugates, particularly antibody drug conjugates (ADCs), to enhance targeted delivery, stability, and potency, as well as for protein drug conjugates using albumin as an alternative to antibodies, to ensure effective and safe delivery of cytotoxic drugs or therapeutic peptides/polypeptides.
Innovation Solution
A nitrogen-containing heterocyclic aromatic ring-based linker with a vinyl substituent is used for site-specific conjugation, providing increased stability and potency in ADCs, and albumin is utilized as a globular protein for targeted drug delivery, leveraging its targeting properties and long half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional linkers (e.g., SMCC, maleimide-based) are used in ADCs, then the conjugation process is well-established, but the stability and potency of the ADC are insufficient
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of the linker to include a nitrogen-containing heterocyclic aromatic ring with a vinyl substituent. This structural parameter change enhances the stability and potency of the ADC while maintaining site-specific conjugation capabilities through the vinyl group's reactivity with thiol-containing amino acids.
Solution Approach 2:
The invention creates a composite linker structure that combines the nitrogen-containing heterocyclic aromatic ring with a vinyl substituent and a drug payload. This composite structure integrates multiple functional elements into a single molecule, achieving both enhanced stability and targeted delivery capabilities.
2Duration of action of stationary object
If antibodies are used as the protein component in ADCs, then targeted delivery to specific tissues is achieved, but the half-life and bioavailability are limited
Solution Approach 1:
The patent extends the application of the nitrogen-containing heterocyclic aromatic ring-based linker beyond antibodies to include albumin and other globular proteins. This universal linker design allows the same conjugation chemistry to be applied to multiple protein types, each offering different pharmacokinetic properties such as albumin's long half-life of approximately 20 days.
Solution Approach 2:
The vinyl-containing linker acts as an intermediary that connects the protein (antibody or albumin) to the drug payload. This intermediary structure enables site-specific conjugation while maintaining the functional properties of both the protein and the drug, allowing for optimized pharmacokinetics depending on the chosen protein carrier.
3Stability of the object's composition
If site-specific conjugation is implemented using vinyl-substituted heterocyclic linkers, then stability is improved, but the manufacturing precision requirements increase
Solution Approach 1:
The patent employs local quality by designing the linker to react specifically with thiol-containing amino acids (such as cysteine) at particular sites on the protein. The nitrogen-containing heterocyclic aromatic ring with vinyl substituent provides localized reactivity at the conjugation site while the rest of the linker structure maintains stability and facilitates drug delivery.
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 new linker system enhances the stability and potency of ADCs, ensuring effective and safe delivery of cytotoxic payloads to target tissues, while albumin-based conjugates offer improved bioavailability and pharmacokinetics for targeted therapy.
Implementation Method 1
a nitrogen containing heterocyclic aromatic ring having a vinyl substituent capable of reacting with at least one thiol group of the protein
Data Source
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AI summary
The present invention relates to protein drug conjugates, methods of manufacturing the same and their use in therapy. In particular, the present invention relates to protein drug conjugates comprising a globular protein, an improved linker and a drug for use in targeted drug delivery applications.