PRMT5 Inhibitor Combination Therapy for Checkpoint Resistance

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Solution Overview

Problem

Cancer cells develop resistance to immune checkpoint blockade (ICB) therapies, and PRMT5 inhibitors are implicated in immune suppression, necessitating a combination therapy to enhance cancer treatment efficacy.

Innovation Solution

Administering a therapeutically effective amount of an immuno-oncology checkpoint inhibitor, such as anti-PD-1 or anti-PD-L1 antibodies, in combination with a PRMT5 inhibitor, particularly methylthioadenosine (MTA)-cooperative PRMT5 inhibitors, to target cancers with MTAP homozygous deletion and KRAS mutations.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If immune checkpoint blockade (ICB) therapy is used alone, then initial immune response is achieved, but cancer cells develop resistance leading to treatment failure

Engineering Contradiction:

Improvetreatment efficacyVSAvoidduration of response

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent combines ICB therapy with PRMT5 inhibition in a dual-therapy approach. The PRMT5 inhibitor and ICB agent are administered together or in sequence to synergistically enhance immune response and overcome resistance mechanisms that develop with monotherapy

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

PRMT5 acts as an intermediary target whose inhibition modifies the tumor microenvironment and immune cell function, thereby enhancing the effectiveness of ICB therapy. The PRMT5 inhibitor prepares the biological system to respond better to checkpoint blockade by reducing immune suppression

Inventive Principle:

Principle #24Intermediary (Mediator)

2Object-affected harmful factors

If PRMT5 inhibitors are used alone, then immune suppression is reduced, but cancer cells maintain resistance to immune checkpoint inhibitors

Engineering Contradiction:

Improveimmune suppressionVSAvoidresponsiveness to ICB

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent merges PRMT5 inhibition with ICB therapy to achieve both reduction of immune suppression and enhancement of ICB responsiveness simultaneously through synergistic interaction between the two mechanisms

Inventive Principle:

Principle #5Merging (Combining)

3Reliability

If combination therapy with PRMT5 inhibitor and ICB is administered, then treatment efficacy is enhanced, but therapy complexity increases

Engineering Contradiction:

Improvetreatment efficacyVSAvoidtherapy complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The combination therapy is segmented into distinct administrable components with defined dosing schedules. The PRMT5 inhibitor and ICB agent can be given at different times or in different formulations, allowing the complex regimen to be broken into manageable segments for clinical implementation

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS20250312344A1Combination therapies using PRMT5 inhibitors and immune checkpoint inhibitors for the treatment of cancer

Publication Date: 2025.10.09 MIRATI THERAPEUTICS INC

AI summary

This disclosure relates to methods of treating cancer. This disclosure further relates to treating cancer in a subject with compounds that are methylthioadenosine (MTA)-cooperative PRMT5 inhibitors, particularly in combination with one or more immuno-oncology checkpoint inhibitors.