Macrocyclic Peptides Disrupt PD-L1 Interactions

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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 protein interactions, leading to immune evasion and exhaustion, which limits the efficacy of treatments for various diseases, including cancer and chronic infections.

Innovation Solution

Development of macrocyclic peptides that specifically bind to PD-L1, inhibiting its interaction with PD-1 and CD80, thereby enhancing immune responses and stimulating antigen-specific T cell activities.

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 protein interactions are not effectively inhibited, leading to immune evasion and exhaustion

Engineering Contradiction:

Improveefficacy of treatmentVSAvoidimmune evasion and exhaustion

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces macrocyclic peptides as intermediary molecules that specifically bind to PD-L1, blocking its interaction with PD-1 and CD80. These peptides act as mediators between the therapeutic agent and the target protein complex, preventing the harmful immune evasion pathway while enhancing immune response.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the molecular parameters of the therapeutic approach by using macrocyclic peptides with specific structural characteristics (cyclic structure, specific amino acid sequences) that enable high-affinity binding to PD-L1. This parameter change in the therapeutic molecule's structure leads to improved binding efficacy and immune modulation.

Inventive Principle:

Principle #35Parameter changes

2Ease of operation

If PD-1/PD-L1 and CD80/PD-L1 interactions are not inhibited, then current therapies can be administered, but T cell function is suppressed and immune responses are diminished

Engineering Contradiction:

Improveadministration of therapyVSAvoidT cell function and immune response

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The macrocyclic peptides are designed to preemptively block the PD-L1 interaction sites before T cell exhaustion can occur. By administering the peptides that pre-bind to PD-L1, the therapy prevents the formation of inhibitory complexes between PD-L1/PD-1 and PD-L1/CD80, thereby preserving T cell function before suppression sets in.

Inventive Principle:

Principle #10Preliminary action

3Reliability

If macrocyclic peptides are developed to specifically bind PD-L1, then immune responses are enhanced, but new therapeutic agents must be developed and tested

Engineering Contradiction:

Improveimmune response enhancementVSAvoiddevelopment and testing of new agents

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent employs macrocyclic peptides as disposable therapeutic agents that can be synthesized through established peptide chemistry methods. These peptides are designed for single-use therapeutic effect, binding to PD-L1 and being cleared after performing their immune-modulating function, eliminating the need for long-term persistence in the body.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Data Source

PatentEP3535280B1immunomodulators

Publication Date: 2022.03.16 BRISTOL MYERS SQUIBB CO

AI summary

The present disclosure provides compounds which are immunomodulators and thus are useful for the amelioration of various diseases, including cancer and infectious diseases.