Bicyclic CD137 Peptide Ligands for High-Affinity Specific Binding
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Solution Overview
Problem
Existing peptide therapeutics targeting CD137 lack the necessary affinity and specificity for effective therapeutic intervention in diseases mediated by this protein target.
Innovation Solution
Development of bicyclic peptide ligands with specific amino acid sequences tethered to a molecular scaffold, forming covalent bonds with cysteine residues to create multiple polypeptide loops, enhancing binding affinity and specificity to CD137.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing immune therapies are used to treat CD137-mediated diseases, then disease treatment is achieved, but lack of specificity and broad immune responses occur leading to adverse effects
Solution Approach 1:
The patent applies local quality by designing peptide ligands with specific amino acid sequences and structures that are tailored to bind exclusively to CD137. The cyclic peptide configuration with specific loop arrangements creates a unique binding interface that targets only CD137-expressing cells, thereby achieving localized therapeutic action without triggering broad immune responses against other tissues.
Solution Approach 2:
The patent utilizes parameter changes by modifying the chemical structure of peptide ligands through cyclization and conjugation to molecular scaffolds. These structural parameter changes enhance binding affinity and specificity to CD137, transforming the peptide from a non-specific binder into a highly selective therapeutic agent that reduces adverse effects.
2Reliability
If peptide ligands are conjugated to molecular scaffolds to increase binding affinity, then specificity and binding affinity are improved, but device complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the therapeutic molecule into distinct functional components: the peptide ligand portion responsible for CD137 binding, the molecular scaffold providing structural stability, and the effector group delivering therapeutic effect. This modular segmentation allows each component to be optimized independently while maintaining overall functionality, managing complexity through functional decomposition.
Solution Approach 2:
The molecular scaffold acts as an intermediary element that bridges the peptide ligand and effector group. This intermediary structure stabilizes the conjugate while preserving the binding affinity of the peptide for CD137, effectively managing the complexity introduced by conjugation through a well-defined intermediate structure.
3Reliability
If cyclic peptide structures are used to reduce conformational flexibility, then binding affinity increases, but manufacturing complexity increases
Solution Approach 1:
The patent applies preliminary action by incorporating cyclization-prone amino acid sequences and reactive groups during the peptide synthesis stage. This preliminary preparation facilitates subsequent cyclization to the molecular scaffold, making the formation of cyclic structures more manageable and less complex than de novo cyclization of linear peptides.
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 bicyclic peptide ligands demonstrate improved binding properties, inhibiting CD137 activity and providing a basis for therapeutic applications in preventing or treating CD137-mediated diseases.
Implementation Method 1
a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold
Implementation Method 2
Cyclic peptides are able to bind with high affinity and target specificity to protein targets... Good binding properties result from a relatively large interaction surface formed between the peptide and the target
Data Source
AI summary
The present invention relates to polypeptides which are covalently bound to molecular scaffolds such that two or more peptide loops are subtended between attachment points to the scaffold. In particular, the invention describes peptides which are high affinity binders of CD137. The invention also includes drug conjugates comprising said peptides, conjugated to one or more effector and/or functional groups, to pharmaceutical compositions comprising said peptide ligands and drug conjugates and to the use of said peptide ligands and drug conjugates in preventing, suppressing or treating a disease or disorder mediated by CD137.