Antibody Drug Conjugates With Enzymatically Cleavable Linkers
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Solution Overview
Problem
Existing antibody-drug conjugates (ADCs) with enzymatically cleavable linkers do not have an optimum activity profile, leading to suboptimal apoptotic action in cancer therapy due to short residence time and high off-target toxicity, primarily because the metabolites formed are substrates of efflux pumps and have high cell membrane permeability.
Innovation Solution
Development of binder-drug conjugates with peptide linkers that can be released by lysosomal tumour-associated enzymes like legumain or cathepsin, featuring a specific toxophore-linker composition that enhances tumour selectivity and reduces systemic cytotoxicity, along with modifications to the kinesin spindle protein inhibitors to maintain potency and target specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If enzymatically cleavable linkers are used in ADCs, then the conjugates can be activated by tumour-associated enzymes, but the activity profile is suboptimal leading to short residence time and high off-target toxicity
Solution Approach 1:
The patent modifies the enzymatically cleavable linker structure by changing the peptide sequence and composition to create linkers with optimized cleavage rates. Specifically, the invention uses peptide linkers with controlled amino acid sequences that are selectively cleaved by tumour-associated proteases at optimal rates, thereby extending residence time in tumour cells while minimizing premature cleavage in normal tissues. This parameter optimization directly addresses the suboptimal activity profile of existing linkers.
Solution Approach 2:
The invention employs composite linker structures that combine enzymatically cleavable peptide segments with non-cleavable spacer regions. These composite linkers feature specific peptide sequences (e.g., containing arginine, lysine, or histidine residues) linked to stable hydrocarbon spacers, creating a hybrid structure that provides both tumour-selective cleavability and controlled stability. This composite approach allows the linker to maintain integrity during circulation while being efficiently cleaved in the tumour microenvironment.
2Speed
If metabolites have high cell membrane permeability, then they can easily enter cells, but they are also substrates of efflux pumps leading to short residence time
Solution Approach 1:
The patent optimizes the physicochemical parameters of the metabolites by modifying the linker composition and drug-linker junction structure. The invention adjusts the hydrophobicity, molecular weight, and charge distribution of the metabolites through careful selection of amino acid sequences and spacer groups, thereby tuning their membrane permeability to an optimal range that balances cellular uptake efficiency with resistance to efflux pump-mediated extrusion.
Solution Approach 2:
The enzymatically cleavable linker acts as an intermediary that controls the timing and location of drug release. By designing linkers that are stable in circulation but rapidly cleaved by tumour-associated proteases, the invention ensures that active metabolites are generated primarily within tumour cells. This spatial and temporal control reduces the exposure of metabolites to efflux pumps in normal tissues while maintaining high intracellular concentrations in tumour cells, thereby extending effective residence time.
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 achieve long-lasting apoptotic action with high activity in tumour cells while minimizing off-target toxicity, thanks to low efflux from tumour cells and controlled re-establishment of cytotoxic effect through enzymatic release, maintaining high potency at the target with minimal impact on physicochemical and pharmacokinetic behaviour.
Implementation Method 1
peptide linkers that can be released by lysosomal tumour-associated enzymes like legumain or cathepsin
Data Source
AI summary
The invention relates to novel binder-drug conjugates (ADCs) having improved properties, to active metabolites of these ADCs and to processes for their preparation. The present invention furthermore relates to the use of these conjugates for the treatment and/or prevention of diseases and to the use of these conjugates for preparing medicaments for treatment and/or prevention of diseases, in particular hyperproliferative and/or angiogenic disorders such as, for example, cancer diseases.