Anti-IL1RAP Antibodies for Selective AML Stem Cell Elimination

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Solution Overview

Problem

Current treatments for acute myeloid leukemia (AML) are ineffective in eliminating leukemia stem cells (LSCs) while sparing normal hematopoietic stem cells, limiting their success.

Innovation Solution

Development of anti-interleukin-1 receptor accessory protein (IL1RAP) antibodies with specific CDR sequences, including heavy and light chain variable domains, to selectively target and destroy LSCs.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If chemotherapy and molecular targeting therapeutics are used to treat AML, then some leukemia cells are killed, but leukemia stem cells (LSCs) are not eliminated and normal hematopoietic stem cells are damaged

Engineering Contradiction:

Improvetreatment effectivenessVSAvoiddamage to normal hematopoietic stem cells

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing antibodies with specific CDR sequences that recognize unique epitopes on IL1RAP expressed by LSCs. This localized specificity ensures that only LSCs expressing the target antigen are eliminated, while normal hematopoietic stem cells lacking this specific antigen expression pattern are spared from damage.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by developing multiple antibody variants with different CDR H1, CDR H2, CDR H3, CDR L1, CDR L2, and CDR L3 sequences. These sequence variations create antibodies with different binding affinities and specificities for IL1RAP, allowing optimization of the therapeutic window to maximize LSC elimination while minimizing off-target effects on normal cells.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If immunotherapy is used to target LSCs, then selective destruction may be achieved, but the antibody must be highly specific to avoid off-target effects

Engineering Contradiction:

Improveselective targeting capabilityVSAvoidantibody structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies segmentation by dividing the antibody structure into distinct functional regions: variable domains (VH and VL) containing six separate CDR regions (H1-H3 and L1-L3), and constant regions. Each CDR segment can be independently optimized for specific binding to IL1RAP epitopes, allowing high selectivity through combinatorial CDR pairing while maintaining a relatively simple overall antibody framework structure.

Inventive Principle:

Principle #1Segmentation

3Ease of operation

If current chemotherapy regimens are used, then treatment can be administered, but the ability to eliminate LSCs is insufficient leading to treatment failure

Engineering Contradiction:

Improvetreatment administrabilityVSAvoidLSC elimination capability

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent employs the intermediary principle by using monoclonal antibodies as mediator molecules that bridge the immune system and LSCs. The antibodies bind specifically to IL1RAP on LSC surfaces, serving as intermediaries that recruit immune effector cells (such as NK cells and macrophages) to selectively eliminate LSCs through antibody-dependent cellular cytotoxicity (ADCC) and other immune mechanisms, thereby enhancing LSC elimination capability while maintaining ease of administration.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS12503513B2IL1RAP antibodies

Publication Date: 2025.12.23 CITY OF HOPE

AI summary

Provided herein are, inter alia, Interleukin-1 receptor accessory protein (IL1RAP) antibodies and fragments thereof which may form part of chimeric antigen receptors or bispsecific antibodies and are useful for treating IL1RAP-expressing cancers.