Glycan-Linked Masked PBD Dimers for Lower-Toxicity ADCs
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Solution Overview
Problem
Current antibody-drug conjugates (ADCs) using pyrrolobenzodiazepine (PBD) dimers face high toxicity and limited therapeutic window due to their high potency, leading to adverse side effects in patients.
Innovation Solution
The coupling of a masked PBD dimer via the glycan of a cell-binding agent, utilizing a linker that includes a cycloaddition reaction product, enhances the efficiency and tolerability of the PBD-payload by selectively releasing the cytotoxic agent in the tumor microenvironment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If PBD dimers are used as cytotoxic payload in ADCs, then high potency and effective cancer treatment are achieved, but high toxicity and adverse side effects occur
Solution Approach 1:
The PBD dimer is masked with a glucuronic acid moiety before conjugation to the antibody, creating a prodrug-like structure that is inactive or less active in circulation. The mask is removed in the tumor microenvironment where beta-glucuronidase enzymes are elevated, releasing the active PBD dimer only where needed. This preliminary masking action prevents premature activation and reduces toxicity while maintaining treatment effectiveness.
Solution Approach 2:
The chemical structure of the PBD dimer is modified by introducing a glucuronic acid mask at the N10 position, changing its pharmacological properties from highly active to masked/less active state in circulation. The enzyme-triggered demasking changes the parameter back to highly active state within the tumor microenvironment, optimizing the balance between potency and toxicity.
2Productivity
If high potency cytotoxic agents are used to improve treatment efficacy, then cancer treatment effectiveness increases, but the therapeutic window becomes limited
Solution Approach 1:
The highly potent PBD dimer is preliminarily masked with glucuronic acid to reduce its activity in circulation, allowing higher doses to be administered without proportionally increasing toxicity. The mask is removed selectively in the tumor microenvironment, maintaining high efficacy while expanding the therapeutic window by decoupling the relationship between dose and toxicity.
Solution Approach 2:
The glucuronic acid mask acts as an intermediary between the highly active PBD dimer and the circulation system. It modulates the pharmacological properties of the payload, allowing safe circulation while maintaining the potential for high efficacy through enzyme-triggered release in the tumor microenvironment.
3Reliability
If PBD dimers are conjugated to antibodies for targeted delivery, then selective tumor eradication is achieved, but premature release in circulation occurs
Solution Approach 1:
The PBD dimer is preliminarily masked with glucuronic acid to prevent premature activation and release in circulation. The mask physically blocks the active site and reduces enzymatic activity, ensuring the payload remains inactive during circulation and only activates after targeted delivery to the tumor microenvironment where beta-glucuronidase enzymes are present.
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 results in more effective cancer treatment with reduced adverse side effects by leveraging the elevated enzyme levels in the tumor microenvironment for controlled payload release.
Implementation Method 1
L comprises at least one -L6-Z— fragment, wherein Z1 is a connecting group comprising the product of a cycloaddition reaction
Implementation Method 2
leveraging the elevated enzyme levels in the tumor microenvironment for controlled payload release
Data Source
AI summary
The inventions concerns conjugates of masked PBD dimers, which are suitable in the treatment of cancers. The inventors found that coupling a masked PBD dimer via a glycan of a cell-binding agent increases the efficiency and tolerability of a PBD-payload. These findings allow for more effective cancer treatment with less adverse side-effects. The invention therefore concerns a conjugate of structure (1):wherein AB is a cell-binding agent; x is 1 or 2; y is 1 or 2; D is a masked PBD dimer payload; and L is a linker that connects AB with D.