Dimeric Macrocyclic Peptides Block PD-1 and PD-L1 Interactions
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Solution Overview
Problem
Current therapies for cancer and infectious diseases, such as cancer and chronic infections, face challenges in effectively inhibiting the PD-1/PD-L1 and PD-L1/CD80 interactions, which contribute to immune evasion and exhaustion, limiting the efficacy of immune responses.
Innovation Solution
Development of macrocyclic compounds that specifically bind to PD-L1, inhibiting its interaction with PD-1 and CD80, thereby enhancing immune responses and potentially treating various diseases, including cancer and infectious diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies are used to block PD-1/PD-L1 interaction, then immune response is enhanced, but treatment efficacy is limited due to inability to simultaneously block PD-L1/CD80 interaction
Solution Approach 1:
The patent combines two separate blocking functions into a single dimeric molecule that can simultaneously inhibit both PD-1/PD-L1 and PD-L1/CD80 interactions. The dimeric structure contains two binding domains that can engage with PD-L1 at different sites, effectively blocking multiple interaction pathways concurrently.
Solution Approach 2:
The dimeric compound is designed to perform multiple functions: it can block both PD-1/PD-L1 and PD-L1/CD80 interactions through its two binding domains. This multi-functional design allows a single agent to address multiple immune checkpoint pathways, enhancing versatility compared to monoclonal antibodies that target only one interaction.
2Reliability
If T cells are activated to fight cancer, then tumor growth is inhibited, but T cell exhaustion occurs due to chronic antigen stimulation
Solution Approach 1:
The dimeric compound applies preliminary anti-action by preemptively blocking both PD-1/PD-L1 and PD-L1/CD80 interactions before T cell exhaustion can occur. By simultaneously inhibiting multiple checkpoint pathways, the compound prevents the development of chronic suppression that leads to exhaustion, maintaining T cell functionality over extended periods.
3Reliability
If single-target PD-1 blockade is implemented, then immune suppression is reversed, but additive effect is not achieved
Solution Approach 1:
The dimeric structure merges two blocking functions into one molecule, enabling simultaneous inhibition of PD-1/PD-L1 and PD-L1/CD80 interactions. This combined approach achieves additive therapeutic effects that exceed the efficacy of single-target blockade by addressing multiple immune suppression pathways concurrently.
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.