Core Construct with Click Chemistry Handles for Selective ADC Linkage
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Solution Overview
Problem
Current molecular constructs for delivering therapeutic agents face challenges in selectively targeting and efficiently delivering cytotoxic drugs to specific disease sites, leading to safety and efficacy issues due to non-selective linkage of cytotoxic molecules to antibodies, resulting in heterogeneous mixtures and unacceptable toxicity.
Innovation Solution
A core construct with a center core comprising lysine residues separated by filler sequences and equipped with azide or alkyne groups, allowing for the use of click chemistry to link targeting and effector elements, enabling precise delivery of therapeutic agents to specific sites through Cu(I) azide-alkyne click chemistry, strain-promoted azide-alkyne click chemistry, or inverse electron demand Diels-Alder reactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If cytotoxic molecules are linked non-selectively to antibodies, then the construction of antibody drug conjugates is simplified, but the heterogeneity of the mixture increases and toxicity becomes unacceptable
Solution Approach 1:
The patent introduces a core construct with pre-installed reactive groups (azide, alkyne, or maleimide) that enable selective subsequent coupling. This preliminary preparation of the core construct with specific chemical handles allows for controlled, selective linkage of cytotoxic molecules later, resolving the contradiction between ease of construction and selectivity by separating the construction into two staged processes.
Solution Approach 2:
The core construct serves as an intermediary molecule between the antibody and the cytotoxic molecule. It contains multiple reactive groups that can selectively couple to both the antibody (via thiol or amine groups) and the cytotoxic molecule (via complementary reactive groups), enabling precise, controlled linkage while simplifying the overall conjugation process through this mediating structure.
2Adaptability or versatility
If multiple reactive groups are installed on a core construct, then the ability to link multiple functional elements is enhanced, but the complexity of the construct increases
Solution Approach 1:
The core construct is designed with multiple identical or similar reactive groups (e.g., multiple azide groups, multiple alkyne groups, or multiple maleimide groups) that can all participate in the same type of click chemistry reaction. This universal reactivity pattern allows the core construct to link multiple different functional elements (antibodies, cytotoxic molecules, imaging agents) using the same chemical mechanism, enhancing versatility without proportionally increasing complexity.
Solution Approach 2:
The patent varies parameters of the core construct such as the number of reactive groups, the type of reactive groups (azide, alkyne, maleimide), and the spacing between groups to optimize the balance between versatility and complexity. By systematically adjusting these parameters, the core construct can be tailored for specific applications while maintaining a relatively simple overall structure.
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 approach allows for the targeted delivery of therapeutic agents to disease sites, enhancing efficacy while minimizing systemic side effects and toxicity, by enabling the precise combination and linkage of targeting and effector elements, thereby improving the pharmacokinetic properties and therapeutic effects.
Implementation Method 1
allowing for the use of click chemistry to link targeting and effector elements, enabling precise delivery of therapeutic agents to specific sites through Cu(I) azide-alkyne click chemistry, strain-promoted azide-alkyne click chemistry, or inverse electron demand Diels-Alder reactions
Data Source
AI summary
The present disclosure provides various core constructs. According to embodiments of the present disclosure, the core construct can be used to configure pharmaceutical molecules. In particular, the core construct may be conjugated with a functional element via the click chemistry.