Macrocyclic Peptides Inhibit PD-L1 Interactions
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Solution Overview
Problem
Current therapies for cancer and infectious diseases, such as cancer immunotherapy using PD-1/PD-L1 blockade, face limitations in effectively inhibiting the PD-1/PD-L1 and CD80/PD-L1 protein-protein interactions, which are crucial for immune evasion by cancer cells and pathogens, and do not adequately address chronic infections or septic shock.
Innovation Solution
Development of macrocyclic peptides that specifically bind to PD-L1, inhibiting its interaction with PD-1 and CD80, thereby enhancing T-cell activity and immune response, offering potential therapeutic benefits for cancer, infectious diseases, and septic shock.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies are used to block PD-1/PD-L1 interactions, then immune response is enhanced, but therapeutic effectiveness is limited and does not adequately address chronic infections or septic shock
Solution Approach 1:
The patent modifies the molecular structure parameters by transitioning from large monoclonal antibodies to smaller peptide-based inhibitors (e.g., changing molecular weight, flexibility, and binding interface characteristics). This structural parameter change enables the inhibitors to achieve both high affinity binding to PD-L1 and improved tissue penetration, thereby enhancing therapeutic effectiveness across multiple disease states including cancer, chronic infections, and septic shock.
Solution Approach 2:
The patent designs peptide inhibitors that can universally block multiple immune checkpoint pathways. The inhibitors are engineered to bind PD-L1 with high affinity while maintaining the capability to interfere with both PD-1/PD-L1 and CD80/PD-L1 interactions simultaneously, providing multi-functional immune modulation that addresses diverse pathological conditions with a single therapeutic agent.
2Productivity
If existing PD-1/PD-L1 blockade therapies are used, then T-cell activity is enhanced, but inhibition of protein-protein interactions is insufficient
Solution Approach 1:
The patent introduces peptide-based molecular intermediaries that serve as precise mediators between the immune system components. These peptides are designed with specific amino acid sequences that act as molecular bridges to disrupt the PD-L1/PD-1 and PD-L1/CD80 protein-protein interactions with high precision. The intermediary peptides achieve superior binding specificity and inhibition precision compared to conventional monoclonal antibodies, thereby enhancing T-cell activity more effectively.
3Productivity
If conventional immunotherapy is used, then immune response is stimulated, but immune evasion by cancer cells and pathogens is not adequately addressed
Solution Approach 1:
The patent employs peptide inhibitors that preemptively block the immune checkpoint pathways before cancer cells or pathogens can exploit them for immune evasion. By administering these high-affinity PD-L1 inhibitors, the therapy proactively prevents the formation of suppressive PD-1/PD-L1 and CD80/PD-L1 interactions, thereby neutralizing the immune evasion mechanism before it can suppress the anti-tumor or anti-pathogen immune response.
Data Source
AI summary
The present disclosure provides novel macrocyclic peptides which inhibit the PD-1/PD-L1 and PD-L1/CD80 protein/protein interaction, and thus are useful for the amelioration of various diseases, including cancer and infectious diseases.