β-Glucuronidase-Cleavable Linkers for Stable Antibody Drug Conjugates
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Solution Overview
Problem
There is a need for antibody drug conjugates with β-glucuronidase-cleavable linkers that can selectively deliver a drug to a biological target with favorable physicochemical properties, including solubility and lipophilicity, to address the non-favorable side effects of microtubule inhibitor therapy in cancer treatment.
Innovation Solution
Conjugates comprising a microtubule inhibitor linked through a β-glucuronidase-cleavable linker, which undergo slower enzymatic cleavage, improving stability, solubility, and reducing off-target toxicity, making them suitable for cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a microtubule inhibitor is used for cancer treatment, then therapeutic effect is improved, but off-target toxicity increases
Solution Approach 1:
The patent introduces an antibody as an intermediary carrier that specifically binds to tumor cells, delivering the microtubule inhibitor only to the target site. This antibody-mediated delivery system acts as a mediator between the drug and tumor cells, enabling selective targeting while protecting healthy tissues from exposure to the toxic agent
Solution Approach 2:
The patent extracts the toxic microtubule inhibitor from systemic circulation and concentrates it at the tumor site through antibody binding. By separating the drug delivery to healthy tissues (eliminated) from tumor tissue delivery (retained), the patent achieves selective toxicity reduction while maintaining therapeutic efficacy
2Reliability
If an enzymatically cleavable linker is used to release free drug at the target, then therapeutic delivery is improved, but stability is reduced
Solution Approach 1:
The patent modifies the chemical parameters of the linker by incorporating a β-glucuronidase-cleavable design with specific chemical bonds that remain stable under physiological conditions but are selectively cleaved by tumor-associated β-glucuronidase enzyme. This parameter change enables the linker to maintain stability during circulation while facilitating controlled drug release at the target site
Solution Approach 2:
The patent introduces dynamic characteristics to the linker system where the chemical stability of the conjugate is maintained during circulation, but the linker dynamically transitions to a cleavable state upon encountering tumor-specific β-glucuronidase enzyme. This dynamic behavior allows the system to adapt its stability properties based on the biological environment
3Productivity
If faster enzymatic cleavage is achieved, then drug release efficiency is improved, but off-target drug release increases
Solution Approach 1:
The patent applies local quality by designing the linker with differential reactivity - the β-glucuronidase-cleavable bond exhibits low reactivity in normal physiological environments (reducing off-target release) but high reactivity specifically in the presence of tumor-associated β-glucuronidase enzyme (enhancing local drug release efficiency). This spatially differentiated chemical reactivity resolves the contradiction between release speed and selectivity
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 conjugates exhibit improved efficacy and tolerability by reducing the release of free drug in off-target tissues, enhancing stability and solubility, and providing a favorable toxicity profile.
Implementation Method 1
β-glucuronidase expression has been identified as being upregulated and typically localised to the lysosome. WO2018031690, WO2007011968 and WO2015182984 disclose certain antibody drug conjugates comprising β-glucuronidase-cleavable linkers.
Data Source
Figure 1A~1B
Figure 1C
Figure 1D~1E
AI summary
The specification relates to conjugates comprising a linker of Formula (IMA): and pharmaceutically acceptable salts thereof. The specification also relates the use of the conjugates for the treatment of diseases such as cancer, and intermediates useful for the synthesis of the conjugates.