Beta-glucuronide Linker Drug Conjugates for Targeted Delivery
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Solution Overview
Problem
Current monoclonal antibody drug conjugates face challenges with linker stability and solubility, leading to premature drug release and toxicity, especially when conjugating hydrophobic drugs, and there is a need for targeted delivery of prodrugs to eliminate cancer cells while minimizing toxicity to non-target cells.
Innovation Solution
Development of ligand drug conjugates with a β-glucuronide-based linker that is cleaved by β-glucuronidase, providing serum stability and targeted delivery of drugs to cancer cells, while being rapidly cleared from the system to reduce systemic toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If hydrazone or disulfide-based linkers are used in ADCs, then the linker can be easily attached to the antibody, but the linker becomes labile in circulation causing premature drug release and systemic toxicity
Solution Approach 1:
The patent changes the chemical structure of the linker from traditional hydrazone or disulfide bonds to a β-glucuronide-based linker with specific chemical parameters (glycosidic bond configuration, molecular weight, hydrophilicity) that provide both stability in circulation and targeted cleavability at the tumor site
Solution Approach 2:
The β-glucuronide moiety acts as an intermediary that provides serum stability while being selectively cleaved by β-glucuronidase at the tumor site, mediating between the requirement for circulation stability and targeted drug release
2Reliability
If peptide-based linkers are used to increase stability, then the linker provides higher serum stability, but the increased hydrophobicity leads to aggregation and non-specific uptake into non-targeted tissues
Solution Approach 1:
The patent modifies the linker's physical-chemical parameters by incorporating a β-glucuronide moiety with specific hydrophilicity characteristics that prevent aggregation while maintaining serum stability, optimizing the balance between stability and solubility
Solution Approach 2:
The linker is designed as a composite structure combining the β-glucuronide moiety with the drug and antibody, creating a molecule with optimized properties that balance hydrophobicity and hydrophilicity to prevent aggregation while maintaining targeted delivery
3Reliability
If β-glucuronide prodrugs are used at high systemic levels for targeted delivery, then the prodrug can be converted to free drug at the tumor site, but high systemic levels are associated with undesired toxicities
Solution Approach 1:
The patent uses the β-glucuronide linker to pre-load the drug in a stable, non-toxic form that is designed to be activated only at the tumor site by β-glucuronidase, preventing premature drug release and systemic toxicity
Solution Approach 2:
The active drug is extracted from the circulation by being conjugated to the antibody via the stable β-glucuronide linker, effectively removing the toxic free drug from the systemic circulation while maintaining targeted delivery capability
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 β-glucuronide-based linker system enhances the stability and solubility of drug conjugates, ensuring targeted delivery and efficient intracellular drug delivery to cancer cells, thereby improving therapeutic efficacy and reducing toxicity to non-target cells.
Implementation Method 1
β-glucuronidase is a UDP-glucuronosyl transferase which is present in the lysosomes of essentially all human tissues. The enzyme catalyzes the hydrolysis of the glycosidic bond of glucuronides
Implementation Method 2
β-glucuronides are metabolites produced in the liver and kidneys by a class of enzymes known as UDP-glucuronosyl transferases. These transferases are involved in a metabolic transformation leading to the clearance of xenobiotics from the body. Glucuronidation dramatically increases the solubility of substrate compounds
Data Source
AI summary
Ligand Drug conjugate compounds comprising a β-glucuronide-based linker and methods of using such compounds are provided.