PD-L1 Binding Polypeptide Scaffold for Tumor Penetration
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Solution Overview
Problem
Current cancer therapies targeting the PD-1/PD-L1 pathway, such as monoclonal antibodies, face limitations in tissue penetration and distribution due to their large size, leading to suboptimal therapeutic efficacy and potential toxicity, while there is a need for improved agents with high affinity for PD-L1 for therapeutic, prognostic, and diagnostic applications.
Innovation Solution
Development of engineered PD-L1 binding polypeptides with specific amino acid sequences, such as ERTX4AX6WEIX10X11LPNLX16X17X18QX20GAFIX25X26LHD, which exhibit high binding affinity (KD ≤ 1 × 10^-6) and can be integrated into three-helix bundle protein domains, enhancing their therapeutic and diagnostic potential.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies are used to target PD-L1, then high binding affinity is achieved, but tissue penetration and distribution are poor due to large molecular size
Solution Approach 1:
The invention extracts only the essential binding motif from the full monoclonal antibody structure. The PD-L1 binding motif (amino acid sequence ERTX4AX6WEIX10X11LPNLX16X17X18QX20GAFIX25X26LHD) is isolated and integrated into a compact three-helix bundle protein domain, removing the large antibody framework while preserving the critical PD-L1 binding capability.
Solution Approach 2:
The invention changes the molecular size parameter by transitioning from a large monoclonal antibody (150 kDa) to a compact polypeptide (5-20 kDa). This parameter change is achieved by redesigning the protein structure as a three-helix bundle, which maintains stability while dramatically reducing molecular dimensions to improve tissue penetration.
2Length of moving object
If smaller polypeptides are used to improve tissue penetration, then distribution is improved, but binding affinity for PD-L1 may be reduced
Solution Approach 1:
The invention performs preliminary optimization of the binding motif sequence before integration into the three-helix bundle structure. The amino acid sequence is specifically designed and validated to ensure high PD-L1 binding affinity is maintained even in the reduced polypeptide format, preventing affinity loss during the size reduction process.
Solution Approach 2:
The invention creates a composite structure by integrating the PD-L1 binding motif with a three-helix bundle protein domain. This composite design combines the specific binding capability of the motif with the structural stability and compactness of the helix bundle, achieving both high affinity and small size simultaneously.
3Reliability
If engineered polypeptides with optimized sequences are developed, then binding affinity is improved, but development complexity increases
Solution Approach 1:
The invention segments the complex design problem into manageable components: (1) identifying the critical PD-L1 binding motif sequence, (2) designing the three-helix bundle scaffold, and (3) integrating the motif into the scaffold. This segmentation simplifies the overall development process while maintaining high binding affinity.
Data Source
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AI summary
The present disclosure relates to a class of engineered polypeptides having a binding affinity for programmed death-ligand 1 (PD-L1), and provides a PD-L1 binding polypeptide comprising the sequence ERTX4AX6WEIX10X11LPNLX16X17X18QX20GAFIX25X26LHD. The present disclosure also relates to the use of such a PD-L1 binding polypeptide a prognostic and/or diagnostic agent as well as a therapeutic agent.