Bicyclic Peptide Ligands for Nectin-4 Targeted Therapy
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Solution Overview
Problem
Current therapeutic options are inadequate for effectively treating advanced malignancies associated with overexpression of Nectin-4 in tissues, particularly in cancers such as non-small-cell lung cancer, ovarian cancer, triple-negative breast cancer, gastric/upper gastrointestinal cancer, and pancreatic cancer, where targeted therapies are limited and standard treatments have failed.
Innovation Solution
A pharmaceutical composition comprising BT8009, a Bicycle toxin conjugate, in combination with histidine, sucrose, and Polysorbate 20, administered via IV infusion, either as a monotherapy or in combination with nivolumab, to target and inhibit Nectin-4-expressing tumors, providing a novel approach for treating advanced solid tumor malignancies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If standard treatments are used for advanced malignancies with Nectin-4 overexpression, then treatment options are limited and have failed, but no effective targeted therapy is available
Solution Approach 1:
The invention segments the therapeutic approach by creating a targeted conjugate system where the bicyclic peptide specifically binds to Nectin-4 on tumor cells, separating the targeting function from the cytotoxic function. This allows selective delivery of the toxin component to Nectin-4 expressing malignancies while sparing normal tissues.
Solution Approach 2:
The bicyclic peptide acts as an intermediary molecule that bridges the gap between the Nectin-4 target on tumor cells and the cytotoxic payload. The peptide-conjugate system serves as a mediator that enables targeted therapy where none previously existed for Nectin-4 positive malignancies.
2Reliability
If cyclic peptide structures are used to achieve high binding affinity and target specificity, then binding properties are improved, but the molecular complexity increases
Solution Approach 1:
The bicyclic peptide structure employs a nested architecture where two cyclic constraints work together to lock the peptide into a specific conformation. This nested cyclic structure (two rings within a single peptide chain) provides enhanced binding affinity and specificity while maintaining a manageable molecular complexity through systematic design.
Solution Approach 2:
The invention optimizes binding properties by changing key parameters of the peptide structure including the specific amino acid sequence, the size and geometry of the cyclic constraints, and the spatial arrangement of binding residues. These parameter optimizations achieve high Nectin-4 affinity while controlling molecular complexity through rational design.
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 composition demonstrates potential clinical activity and safety in Phase I/II studies, offering a new therapeutic option for patients with advanced malignancies that have progressed beyond standard treatments, with preliminary signals of anti-tumor activity and manageable side effects.
Implementation Method 1
Cyclic peptides are able to bind with high affinity and target specificity to protein targets
Implementation Method 2
The reduced flexibility also leads to locking target-specific conformations, increasing binding specificity compared to linear peptides
Implementation Method 3
administering to the patient weekly by IV infusion a pharmaceutical formulation comprising BT8009
Data Source
AI summary
The present invention relates to a Bicycle toxin conjugate BT8009, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, and uses thereof. In one embodiment, the pharmaceutical composition comprises BT8009, histidine, sucrose and Polysorbate 20. In another embodiment, the pharmaceutical composition is for use in treating an advanced solid tumor malignancy associated with Nectin-4-expression in a patient, preferably in combination with Nivolumab.