Macrocyclic Peptides Inhibit PD-1/PD-L1 Interactions

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Solution Overview

Problem

Current therapies for cancer and infectious diseases, such as cancer immunotherapy, face challenges in effectively inhibiting the PD-1/PD-L1 and CD80/PD-L1 protein interactions, which are crucial for immune evasion by tumor cells and pathogens, limiting the enhancement of immune responses.

Innovation Solution

Development of novel macrocyclic peptides that specifically inhibit the interaction between PD-L1 and PD-1 or CD80, enhancing T cell functional activity and immune stimulation, offering potential therapeutic formulations for various diseases including cancer and infectious diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If monoclonal antibodies are used to block PD-1/PD-L1 interaction, then immune response enhancement is achieved, but therapy cost and administration complexity increase

Engineering Contradiction:

Improveimmune response enhancementVSAvoidtherapy administration complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent employs small molecule compounds instead of expensive monoclonal antibodies. These small molecules are designed to be cost-effective, disposable alternatives that achieve the same immunomodulatory effect without the high cost and complexity associated with monoclonal antibody therapies

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The invention changes the molecular parameters from large protein-based monoclonal antibodies to smaller synthetic compounds. This parameter change enables oral administration, simplified dosing regimens, and reduced manufacturing complexity while maintaining therapeutic efficacy in blocking PD-1/PD-L1 and CD80/PD-L1 interactions

Inventive Principle:

Principle #35Parameter changes

2Reliability

If PD-1/PD-L1 interaction is blocked to enhance T cell activity, then cancer treatment efficacy improves, but off-target immune activation and side effects may occur

Engineering Contradiction:

Improvecancer treatment efficacyVSAvoidoff-target immune activation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The small molecule compounds are designed to act locally at the tumor microenvironment where PD-1/PD-L1 and CD80/PD-L1 interactions occur. The compounds concentrate their immunomodulatory effect at the target site, enhancing T cell activity against tumor cells while minimizing systemic off-target immune activation and associated side effects

Inventive Principle:

Principle #3Local quality

3Measurement precision

If novel macrocyclic peptides are developed to specifically inhibit PD-L1 interactions, then binding specificity improves, but manufacturing complexity and development time increase

Engineering Contradiction:

Improvebinding specificityVSAvoidcompound synthesis complexity

Core Design Contradiction:

Measurement precisionVSEase of manufacture

Solution Approach 1:

The patent employs macrocyclic peptide structures that combine the high binding specificity of peptide-based therapeutics with the stability and manufacturability of cyclic structures. This composite approach achieves nanomolar binding affinity to PD-L1 while maintaining feasibility for chemical synthesis and pharmaceutical manufacturing

Inventive Principle:

Principle #40Composite materials

Data Source

PatentEP3271373B1immunomodulators

Publication Date: 2022.03.16 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.