IL1RAP-Targeting Antibodies for CML Stem Cell Elimination

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Solution Overview

Problem

Current treatments for chronic myeloid leukemia (CML) are limited by the resistance of CML stem cells to tyrosine kinase inhibitors, and no cell surface biomarker has been identified to distinguish CML stem cells from normal hematopoietic stem cells, making it difficult to develop effective therapeutic strategies.

Innovation Solution

Development of antibodies or antigen-binding fragments specific to interleukin-1 receptor accessory protein (IL1RAP) to target and inhibit CML stem cells, which express higher levels of IL1RAP on their surface, allowing for the differentiation and elimination of these cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If tyrosine kinase inhibitors are used to treat CML, then the treatment can target BCR/ABL1 positive cells, but CML stem cells develop resistance and are not effectively eliminated

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidstem cell resistance

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts and targets a specific distinguishing feature of CML stem cells - the overexpression of IL1RAP on their surface. By using antibodies that specifically bind to IL1RAP, the treatment can selectively identify and eliminate CML stem cells that were previously resistant to tyrosine kinase inhibitors, without affecting normal stem cells that do not overexpress IL1RAP

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent applies local quality by creating a differentiated treatment approach where the same antibody therapy selectively affects only the pathological CML stem cells based on their unique IL1RAP overexpression characteristic, while sparing normal stem cells. This localized targeting based on specific molecular expression patterns resolves the resistance problem

Inventive Principle:

Principle #3Local quality

2Object-affected harmful factors

If normal hematopoietic stem cells are targeted for elimination, then leukemia cells can be removed, but normal stem cell function is compromised and healthy blood cell production is affected

Engineering Contradiction:

Improveleukemia cell eliminationVSAvoidnormal stem cell function

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent utilizes the local quality principle by exploiting the differential expression of IL1RAP between pathological and normal stem cells. CML stem cells overexpress IL1RAP on their surface, while normal hematopoietic stem cells do not or express it at low levels. This allows the antibody therapy to selectively target and eliminate only the leukemic cells while preserving normal stem cell function and healthy blood cell production

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs an antibody as an intermediary agent that specifically recognizes and binds to the IL1RAP protein on the surface of CML stem cells. This intermediary enables selective identification and elimination of pathological cells through immune-mediated mechanisms, while the specificity of antibody-antigen binding ensures that normal stem cells without IL1RAP overexpression are not targeted, thus preserving normal hematopoietic function

Inventive Principle:

Principle #24Intermediary (Mediator)

3Adaptability or versatility

If no cell surface biomarker is used to distinguish CML stem cells, then treatment can be broadly applied, but it is impossible to selectively target leukemic cells without affecting normal cells

Engineering Contradiction:

Improvetreatment applicabilityVSAvoidcell differentiation capability

Core Design Contradiction:

Adaptability or versatilityVSMeasurement precision

Solution Approach 1:

The patent introduces IL1RAP as a specific cell surface biomarker that serves as an intermediary identifier for CML stem cells. This biomarker enables precise detection and differentiation of leukemic stem cells from normal hematopoietic stem cells through antibody binding, providing the measurement precision needed for selective targeting while maintaining treatment versatility across different CML cases

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent employs flow cytometry and other detection methods that utilize fluorescently labeled antibodies binding to IL1RAP, effectively creating a 'color change' or signal change that distinguishes IL1RAP-positive CML stem cells from IL1RAP-negative normal stem cells. This enables visual and quantitative differentiation of cell populations for precise therapeutic targeting

Inventive Principle:

Principle #32Color changes

Data Source

PatentEP2985293B1Il1RAP expression on acute and chronic myeloid leukemia cells

Publication Date: 2022.11.30 CANTARGIA

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AI summary

The present invention provides agents comprising or consisting of a binding moiety with specificity for interleukin-1 receptor accessory protein (IL1RAP) for use in inducing cell death and/or inhibiting the growth and/or proliferation of pathological stem cells and/or progenitor cells associated with a neoplastic hematologic disorder, wherein the cells express IL1RAP. A related aspect of the invention provides agents comprising or consisting of a binding moiety with specificity for interleukin-1 receptor accessory protein (IL1RAP) for use in detecting pathological stem cells and/or progenitor cells associated with a neoplastic hematologic disorder, wherein the cells express IL1RAP. Further provided are pharmacological compositions comprising the agents of the invention and methods of using the same.