CLEVER-1 Antibody Modulates M2 to M1 Macrophage Phenotype

Solution Overview

Problem

Current cancer therapies targeting tumour-associated macrophages often result in systemic toxicities and paradoxically can promote tumour growth, as they affect all macrophages rather than specifically modulating M2 macrophages into M1 macrophages, leading to ineffective treatment with harmful side effects.

Innovation Solution

An antibody or fragment capable of binding to specific epitopes on the CLEVER-1 protein, such as PFTVLVPSVSSFSSR and QEITVTFNQFTK, is used to modulate M2 macrophages into M1 macrophages, thereby activating the immune system to combat cancer by increasing TNF-alpha secretion and HLA-DR expression, specifically targeting tumour-associated macrophages.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current cancer therapies target all macrophages to modulate M2 into M1 phenotype, then tumour growth inhibition is improved, but systemic toxicities and paradoxical tumour growth promotion occur

Engineering Contradiction:

Improvetumour growth inhibitionVSAvoidsystemic toxicities

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by using CLEVER-1 antibodies that specifically target tumour-associated macrophages (TAMs) expressing CLEVER-1 on their surface, rather than affecting all macrophages systemically. This localized targeting ensures that only the pathogenic M2 macrophages in the tumour microenvironment are modulated to M1 phenotype, while healthy macrophages in other tissues remain unaffected, thereby eliminating systemic toxicities while maintaining tumour growth inhibition efficacy

Inventive Principle:

Principle #3Local quality

2Reliability

If current cancer therapies target all macrophages to modulate M2 into M1 phenotype, then tumour growth inhibition is improved, but paradoxical tumour growth promotion occurs

Engineering Contradiction:

Improvetumour growth inhibitionVSAvoidparadoxical tumour growth promotion

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by using CLEVER-1 antibodies that specifically target tumour-associated macrophages (TAMs) expressing CLEVER-1 on their surface, rather than affecting all macrophages systemically. This localized targeting ensures that only the pathogenic M2 macrophages in the tumour microenvironment are modulated to M1 phenotype, while healthy macrophages in other tissues remain unaffected, thereby eliminating systemic toxicities while maintaining tumour growth inhibition efficacy

Inventive Principle:

Principle #3Local quality

3Quantity of substance

If non-specific macrophage targeting is used, then treatment coverage is improved, but treatment precision deteriorates

Engineering Contradiction:

Improvetreatment coverageVSAvoidtreatment precision

Core Design Contradiction:

Quantity of substanceVSManufacturing precision

Solution Approach 1:

The patent applies local quality by using CLEVER-1 antibodies that specifically target tumour-associated macrophages (TAMs) expressing CLEVER-1 on their surface, rather than affecting all macrophages systemically. This localized targeting ensures that only the pathogenic M2 macrophages in the tumour microenvironment are modulated to M1 phenotype, while healthy macrophages in other tissues remain unaffected, thereby eliminating systemic toxicities while maintaining tumour growth inhibition efficacy

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent uses CLEVER-1 antibody as an intermediary that specifically binds to CLEVER-1 expressed on TAMs, serving as a selective mediator to trigger phenotypic switching only in target cells. This intermediary approach enables precise delivery of the therapeutic effect (M2 to M1 switching) exclusively to tumour-associated macrophages, achieving both high treatment coverage of TAMs and high precision by sparing other macrophage populations

Inventive Principle:

Principle #24Intermediary (Mediator)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This approach effectively modulates M2 macrophages into M1 macrophages, enhancing T-cell activation and reducing cancer-related immune suppression, allowing for targeted treatment of cancer and prevention of metastasis with reduced side effects, and can also be applied to chronic infections by removing immune suppression against infective antigens.

Implementation Method 1

an antibody or fragment(s) thereof capable of binding to human CLEVER-1

Methodology Applied

Scientific EffectAntibody-antigen binding:

Implementation Method 2

measuring macrophage/monocyte TNF-alpha secretion

Methodology Applied

Scientific EffectCytokine secretion:

Data Source

PatentEP3445786B1Diagnosis of immune activation using clever-1, TNF-alpha and HLA-dr binding agents

Publication Date: 2023.10.04 FARON PHARMA OY

Figure 1A~1B
Figure 2A~2B

AI summary

An agent capable of binding to CLEVER-1 in an individual can be used in activating macrophages to switch their phenotype from M2 macrophages into M1 macrophages. The invention relates to methods for utilizing the macrophages ability to switch their phenotype. In one aspect, the invention relates to a method for estimating of the efficacy of anti-CLEVER-1 therapy by monitoring a modulation of M2 macrophages into M1 macrophages, when an agent capable of binding to CLEVER-1 is administered in a patient, wherein an increased TNF-alpha secretion or HLA-DR expression is indicative of modulation of M2 macrophages into M1 macrophages.