Traceless Linkers for Antibody Drug Conjugates
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current therapies for targeting protein-protein interactions (PPIs) and degrading 'undruggable' proteins are challenging due to issues with selective targeting of diseased tissues and cells, and the need for compounds that can induce desirable PPIs and protein degradation.
Innovation Solution
Development of conjugates comprising a compound that induces protein-protein interactions linked to a cleavable linker and a binding moiety, such as an antibody, capable of specifically binding to a protein, allowing for targeted protein degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If a cleavable linker is used in antibody drug conjugates to release therapeutic payload at target site, then the ability to release payload upon internalization is improved, but premature cleavage during circulation occurs reducing stability
Solution Approach 1:
The patent employs parameter changes by designing linkers with specific chemical structures (e.g., disulfide bonds, hydrolyzable esters, peptide sequences) that have controlled stability characteristics. The linker parameters such as bond strength, hydrophobicity, and enzymatic susceptibility are tuned to achieve optimal balance between circulation stability and intracellular cleavage efficiency.
Solution Approach 2:
The cleavable linker acts as an intermediary component between the antibody and therapeutic payload. It mediates the conditional connection, remaining stable during circulation but facilitating payload release under specific intracellular conditions such as reduced environment, enzymatic presence, or pH changes.
2Adaptability or versatility
If targeted protein degraders are used to degrade undruggable proteins, then the ability to target previously undruggable proteins is improved, but selective targeting of diseased tissues and cells becomes challenging
Solution Approach 1:
The patent merges two functional components: an antibody or cell-binding agent that provides high specificity for diseased cells, and a targeted protein degrader (PROTAC or molecular glue) that induces protein degradation. This combination allows the conjugate to first selectively bind to diseased cells via the binding agent, then induce degradation of the target protein through the degrader component, thereby achieving both selective targeting and protein degradation capability.
3Ease of operation
If known traceless linkers are used that require UV light activation or chemical triggers, then the ability to activate payload release is improved, but the stability half-life becomes too short (minutes to hours) or harmful byproducts are generated
Solution Approach 1:
The patent designs linkers that utilize endogenous cellular conditions (such as intracellular reducing environment, specific enzymes like glutathione or proteases, or pH gradients) to automatically trigger payload release. This self-service mechanism eliminates the need for external UV light activation or chemical triggers, thereby maintaining linker stability during circulation while enabling autonomous payload release upon cellular internalization.
Data Source
AI summary
The present disclosure provides traceless linkers, which can link an inducer of protein-protein interaction to a cell binding agent. Also provided are compositions comprising the linked compounds. The compounds and compositions are useful for treating diseases such as cancer in subjects in need thereof.