Modular Linker Compounds for ADCs with Cleavable Peptide Spacers
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Solution Overview
Problem
Current linker compounds for target-binding drug conjugates (TBDCs) face challenges in achieving stable conjugation, adaptable Drug-Antibody-Ratio (DAR), and aqueous solubility, which affects the therapeutic index and pharmacokinetics of antibody-drug conjugates (ADCs).
Innovation Solution
The development of modular linker compounds with a cleavable peptide sequence, self-immolative spacer, solubility enhancing group, and a multimeric core that allows for customizable Drug-Antibody-Ratio (DAR) and aqueous solubility, ensuring stable conjugation and efficient drug delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional linker compounds are used to ensure stable conjugation, then plasma stability is improved, but adaptability in Drug-Antibody-Ratio (DAR) and aqueous solubility deteriorates
Solution Approach 1:
The linker compound is divided into distinct functional modules: a stable conjugation moiety for plasma stability, a cleavable peptide sequence for controlled release, a self-immolative spacer for efficient payload release, and solubility enhancing groups for aqueous solubility. This segmentation allows each module to independently optimize its function while working together as an integrated system.
Solution Approach 2:
The modular linker compound is designed to perform multiple functions simultaneously: stable conjugation in plasma, controlled cleavage in target cells, self-immolation for payload release, and enhancement of aqueous solubility. This multi-functionality within a single linker structure resolves the contradiction between stability and adaptability.
2Reliability
If linker compounds are designed for stable conjugation, then conjugation stability is improved, but aqueous solubility deteriorates
Solution Approach 1:
Different regions of the linker compound have specialized properties: the conjugation moiety provides stability, while solubility enhancing groups (such as hydrophilic spacers or polar functional groups) are strategically positioned to improve aqueous solubility without compromising the stability of the conjugation site.
Solution Approach 2:
The linker compound combines multiple chemical moieties with different properties into a composite structure: stable conjugation groups combined with solubility enhancing groups creates a hybrid molecule that simultaneously achieves both stability and solubility.
3Object-generated harmful factors
If modular linker compounds with solubility enhancing groups are used, then aqueous solubility is improved, but device complexity increases
Solution Approach 1:
The linker is segmented into standardized functional modules that can be independently designed and assembled. This modular approach makes the complexity manageable through systematic design rather than monolithic construction, allowing each module to be optimized separately.
Solution Approach 2:
The solubility enhancing groups are introduced by modifying specific parameters of the linker structure (such as adding hydrophilic functional groups or adjusting molecular polarity) rather than fundamentally redesigning the entire linker, thereby managing complexity through targeted parameter optimization.
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 modular linker compounds enable homogeneous Degree-of-Labelling (DOL) and adaptable DAR, improving the therapeutic index and pharmacokinetics of TBDCs, while ensuring efficient and specific delivery of cytotoxic drug substances to cancer cells.
Implementation Method 1
a self-immolative spacer, to which both a solubility enhancing group and the cytotoxic drug substance are bound in physical proximity
Implementation Method 2
a cleavable peptide sequence connected to a self-immolative spacer
Data Source
AI summary
The present disclosure relates to modular linker compounds for target-binding drug conjugates (TBDCs) and in particular to modular linker compounds for antibody-drug-conjugates (ADCs). The present disclosure further relates to methods of synthesizing the modular linker compound, to target-binding drug conjugates comprising the modular linker compound of the present disclosure as well as to pharmaceutical compositions comprising target-binding drug conjugates compound of the present disclosure. Embodiments of the present disclosure have been particularly developed as target-binding drug conjugates for use in the treatment of cancer and will be described hereinafter with reference to this application. However, it will be appreciated that the present disclosure is not limited to this particular field of use.