LCOR Mutants Without NRB Domain for Antigen Presentation in TNBC

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Solution Overview

Problem

Existing cancer immunotherapy strategies, such as immune-checkpoint blockade (ICB) and adoptive cell transfer (ACT), face resistance and limited efficacy in treating Triple Negative Breast Cancer (TNBC) due to tumor-intrinsic mechanisms, particularly the downregulation of antigen presentation machinery (APM) by cancer stem cells (CSCs).

Innovation Solution

Utilization of a Ligand-dependent corepressor (LCOR) or its mutants and fragments, specifically those lacking a Nuclear Receptor Binding Domain, to transcriptionally induce APM genes, enhancing immune recognition and vulnerability of CSCs to immune attack.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If immune-checkpoint blockade (ICB) therapy is used to treat TNBC, then antitumor immune responses are unleashed, but tumor-intrinsic mechanisms cause resistance and limit efficacy

Engineering Contradiction:

Improveefficacy of ICB therapyVSAvoidtumor resistance to ICB

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies preliminary action by overexpressing LCOR in tumor cells before ICB therapy administration. This pre-treatment upregulates APM genes and enhances MHC-I expression, preparing the tumor cells for immune recognition. The LCOR overexpression creates a permissive state that enables subsequent ICB therapy to be effective, preventing the tumor from resisting immune attack during treatment.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent uses LCOR as an intermediary molecule that mediates between the tumor cells and the immune system. LCOR overexpression acts as a bridge that enhances APM gene transcription and MHC-I surface presentation, thereby facilitating immune recognition of tumor antigens. This intermediary mechanism converts non-immunogenic tumor cells into immunogenic ones that respond to ICB therapy.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Object-affected harmful factors

If cancer stem cells (CSCs) downregulate antigen presentation machinery (APM) to evade immune surveillance, then immune evasion is achieved, but immune recognition and vulnerability to immune attack are reduced

Engineering Contradiction:

Improveimmune evasion by CSCsVSAvoidimmune recognition of CSCs

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent applies inversion by reversing the downregulation mechanism. Instead of allowing CSCs to suppress APM expression, the patent uses LCOR overexpression to actively upregulate APM genes. This inverted approach counteracts the natural immune evasion strategy of CSCs, forcing them to present antigens and become visible to the immune system, thereby converting immune evasion into immune recognition.

Inventive Principle:

Principle #13The other way round (Inversion)

3Reliability

If APM genes are not sufficiently expressed in tumor cells, then immune surveillance evasion occurs, but immune recognition and therapeutic response are compromised

Engineering Contradiction:

Improveimmune surveillance efficacyVSAvoidAPM gene expression level

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent applies parameter changes by modifying the expression level of APM genes through LCOR overexpression. The patent specifically increases MHC-I, TAP1, and β2-microglobulin expression levels in tumor cells. This parameter modification transforms the biochemical state of tumor cells from low APM expression to high APM expression, enabling effective immune recognition and response to immunotherapy.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP4711380A1Ligand-dependent corepressor, (LCOR), mutants and fragments thereof, and uses for cancer therapy

Publication Date: 2026.03.18 MEDICAL RES HOSPITAL INST FOUNDATION

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AI summary

The present invention provides a novel and improved cancer therapy based on an isolated or synthesized polynucleotide sequence coding for a mutant of a Ligand-dependent corepressor (LCOR), or a fragment thereof, capable of inducing expression of the antigen processing/presentation machinery (APM) genes, wherein the mutant or fragment of a Ligand-dependent corepressor (LCOR) is characterized by comprising a functional HTH domain, and wherein said mutant or fragment of a Ligand-dependent corepressor (LCOR) is further characterized by comprising an absent or inactivated Nuclear Receptor Binding Domain.