Macrocyclic Compounds Blocking PD-L1 Interactions

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Solution Overview

Problem

Current treatments 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 suppression, which limits the efficacy of immunotherapies.

Innovation Solution

Development of macrocyclic compounds that specifically bind to PD-L1, inhibiting its interaction with PD-1 and CD80, thereby enhancing T cell activity and immune response.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments are used to address PD-1/PD-L1 and CD80/PD-L1 interactions, then immune suppression occurs, but the treatments fail to effectively inhibit the protein interactions

Engineering Contradiction:

Improveefficacy of immunotherapyVSAvoidimmune evasion and suppression

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent employs monoclonal antibodies with modified binding parameters to PD-L1, achieving higher affinity and specificity compared to current treatments. These antibodies are engineered to optimally block both PD-1 and CD80 interactions with PD-L1, thereby resolving the contradiction between effective interaction inhibition and preventing immune suppression

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces monoclonal antibodies as intermediary molecules that specifically bind to PD-L1, preventing direct interaction between PD-L1 and its partners PD-1 and CD80. This intermediary approach effectively blocks the immunosuppressive pathway without directly interfering with T cell activation mechanisms

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If PD-1/PD-L1 interaction is blocked to enhance T cell activity, then immune response is improved, but current methods lack sufficient inhibition efficacy

Engineering Contradiction:

ImproveT cell functional activityVSAvoidinhibition efficacy

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent describes monoclonal antibodies that simultaneously block both PD-1 and CD80 interactions with PD-L1, providing multi-functional inhibition. This universal approach ensures comprehensive blockade of immunosuppressive pathways while maximizing T cell activation potential, thereby achieving both high productivity and reliability

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Reliability

If PD-L1 interaction with PD-1 and CD80 is inhibited to prevent immune evasion, then cancer and infectious disease treatment is enhanced, but current treatments fail to achieve effective blockade

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidimmune evasion

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent utilizes monoclonal antibodies with optimized binding parameters including higher affinity constants and improved pharmacokinetic properties. These parameter changes enable effective blockade of PD-L1 at therapeutic concentrations, preventing immune evasion mechanisms while enhancing therapeutic efficacy against cancer and infectious diseases

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP3423470B1immunomodulators

Publication Date: 2021.08.18 BRISTOL MYERS SQUIBB CO

AI summary

The present disclosure provides novel macrocyclic compounds 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.