Macrocyclic Peptides Block PD-1/PD-L1 Interaction

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Solution Overview

Problem

Current therapies for cancer and infectious diseases often fail to effectively inhibit the PD-1/PD-L1 and CD80/PD-L1 interactions, leading to immune evasion and suppression, which limits the efficacy of treatments for various diseases, including cancer and chronic infections.

Innovation Solution

Development of macrocyclic peptides that specifically inhibit the interaction between PD-L1 and PD-1 or CD80, enhancing T cell functional activity and immune response by blocking these interactions, thereby offering a therapeutic approach for cancer and infectious diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current therapies are used to treat cancer and infectious diseases, then treatment is provided, but the PD-1/PD-L1 and CD80/PD-L1 interactions are not effectively inhibited, leading to immune evasion and suppression

Engineering Contradiction:

Improveefficacy of treatmentsVSAvoidimmune evasion and suppression

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs macrocyclic peptides as intermediary molecules that specifically bind to PD-L1, preventing its interaction with PD-1 and CD80. These peptide intermediaries disrupt the harmful immune evasion pathway by occupying the binding site on PD-L1, thereby restoring T cell functionality without requiring direct modification of the receptor-ligand interface itself

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention alters the molecular parameters of the therapeutic agents by using macrocyclic peptides with specific structural characteristics (cyclic structure, particular amino acid sequences) that enable high-affinity binding to PD-L1. This parameter change in the therapeutic molecule's structure allows for effective blockade of the PD-1/PD-L1 and CD80/PD-L1 interactions, overcoming the inadequacy of current therapies

Inventive Principle:

Principle #35Parameter changes

2Reliability

If the interaction between PD-1 and PD-L1 is blocked to reverse immune suppression, then T cell activity is enhanced, but the complexity of the therapeutic approach increases

Engineering Contradiction:

ImproveT cell functional activityVSAvoidtherapeutic approach complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent extracts the essential functional element needed for immune modulation by using isolated macrocyclic peptides that specifically target PD-L1. Rather than employing complex combination therapies or modifying entire immune pathways, the invention extracts and utilizes only the critical PD-L1 binding interaction to achieve immune suppression reversal, thereby simplifying the therapeutic approach while maintaining efficacy

Inventive Principle:

Principle #2Taking out (Extraction)

Data Source

PatentUS11066445B2Immunomodulators acting as antagonists of PD-1

Publication Date: 2021.07.20 BRISTOL MYERS SQUIBB CO

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.