Cyclic PEG Linker for Stable Therapeutic Conjugates
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Solution Overview
Problem
Conjugates used in therapeutic, diagnostic, and labelling applications often face issues with storage stability, biological activity, and conjugation efficiency, particularly when cleavable linkers are used, leading to instability and aggregation during storage and in vivo applications.
Innovation Solution
The use of PEG-containing linkers with a specific structure, featuring at least two (CH2—CH2—O—) units within a ring attached via a single or multiple tethering atoms, enhances the stability and potency of conjugates by allowing more flexible conformations and improved homogeneity during the conjugation process.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional PEG linkers are used in conjugates, then conjugation efficiency is improved, but storage stability deteriorates due to aggregation and instability
Solution Approach 1:
The patent changes the structural parameters of the PEG linker by incorporating it into a ring structure with specific tethering atoms, transforming the linear flexible chain into a cyclic structure with controlled conformational freedom. This parameter change maintains conjugation efficiency while dramatically improving storage stability by reducing aggregation
Solution Approach 2:
The linker is segmented into distinct functional regions: a PEG-containing ring portion providing stability, a tethering atom for protein attachment, and a payload attachment portion. This segmentation allows each region to optimize its function independently, resolving the contradiction between conjugation efficiency and storage stability
2Duration of action of moving object
If cleavable linkers are used to enable payload release, then therapeutic efficacy is improved, but stability during storage and in vivo application deteriorates
Solution Approach 1:
The conjugate is designed with a stable PEG ring linker that maintains structural integrity during storage and in vivo circulation. The cleavable functionality is built into the design but remains dormant until triggered by specific intracellular conditions, achieving preliminary stabilization before payload release is needed
Solution Approach 2:
Different portions of the linker have different qualities: the PEG ring portion provides stability and resistance to aggregation, while the payload attachment portion contains the cleavable bond. This local differentiation allows the linker to simultaneously achieve stability during storage and payload release upon activation
3Ease of operation
If linear PEG chains are used in linkers, then flexibility is improved, but homogeneity during conjugation deteriorates
Solution Approach 1:
The patent transforms the linear PEG chain into a cyclic (ring) structure, changing its geometric form from straight/flexible to curved/constrained. This curvature provides the flexibility needed for conjugation while the cyclic structure imposes conformational constraints that promote homogeneous reaction products
Data Source
AI summary
A conjugate comprising a protein or peptide conjugated to a therapeutic, diagnostic or labelling agent via a linker, characterised in that the linker includes at least two ˜(CH2—CH2—O—)˜ units within a ring, said ring being attached via a single tethering atom within the ring to the rest of the linker, or said ring being attached via two or more tethering atoms within the ring to the rest of the linker at a single point.