Tripeptide ADC Linkers for Stable Circulation and Controlled Payload Release
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Solution Overview
Problem
Existing antibody-drug conjugates (ADCs) face issues with premature payload release due to linker instability, leading to adverse effects such as myelosuppression and liver toxicity, complicating preclinical and clinical applications.
Innovation Solution
Development of peptide linkers with specific structures and functionalities to enhance stability and control payload release within target cells, minimizing adverse effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If valine-based linkers (VCit) are used in ADCs, then payload release efficiency inside target cells is improved, but linker stability in circulation deteriorates due to susceptibility to extracellular carboxylesterase 1c (Ces1c)
Solution Approach 1:
The patent changes the amino acid parameters of the linker by substituting valine with other amino acids (e.g., alanine, glycine, serine) to create alternative linkers that maintain payload release efficiency while improving circulation stability by reducing susceptibility to Ces1c enzymatic degradation
Solution Approach 2:
The patent creates composite linker structures combining multiple amino acid residues with different properties, where the composite structure achieves both stable circulation (through resistant amino acid composition) and efficient payload release (through designed cleavage sites recognized by intracellular enzymes)
2Reliability
If valine-based linkers (VCit) are used in ADCs, then payload release inside target cells is enhanced, but antigen-independent toxicities increase leading to dose-limiting side effects
Solution Approach 1:
The patent modifies the chemical parameters of the linker by replacing valine with amino acids that have different metabolic pathways and enzymatic recognition profiles, thereby reducing off-target toxicity while preserving the intended payload release function in target cells
Solution Approach 2:
The patent converts the potential harm of linker instability into a benefit by designing linkers that are intentionally unstable to specific intracellular enzymes (providing targeted payload release) while being stable to extracellular enzymes (avoiding premature release and toxicity), thus turning the dual-nature of linker stability into a therapeutic advantage
3Ease of manufacture
If rodent models are used for preclinical evaluation, then preclinical testing is enabled, but evaluation accuracy deteriorates due to premature payload release in rodent plasma
Solution Approach 1:
The patent changes the biochemical parameters of the linker to achieve species-independent stability by selecting amino acid compositions that resist degradation by both rodent and human plasma enzymes, thereby enabling accurate preclinical evaluation in rodent models that translates to human clinical outcomes
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 new peptide linkers improve the safety and efficacy of ADCs by reducing premature payload release, thereby minimizing side effects and enhancing therapeutic efficacy.
Implementation Method 1
their susceptibility to extracellular carboxylesterase 1c (Ces1c) in rodent plasma causes premature payload release in circulation
Implementation Method 2
Cleavable linkers are used for nearly 80% of ADCs to efficiently liberate conjugated payloads inside the target cancer cells
Data Source
AI summary
Provided herein are peptide linkers which may be used to prepare drug conjugates, drug conjugates prepared using these linkers, and compositions and methods of treatment thereof.