Anti-IL1RAP Antibodies for Selective AML Stem Cell Elimination
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Solution Overview
Problem
Current treatments for acute myeloid leukemia (AML) are limited in effectiveness due to the inability to specifically target and eliminate leukemia stem cells (LSCs) while sparing normal hematopoietic stem cells, leading to incomplete treatment success.
Innovation Solution
Development of an anti-interleukin-1 receptor accessory protein (IL1RAP) antibody and recombinant proteins with specific variable domains that target IL1RAP on leukemia cells, allowing for selective destruction of LSCs while sparing normal hematopoietic stem cells, using a bispecific antibody approach to facilitate T-cell activation and cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If chemotherapy and molecular targeting therapeutics are used to treat AML, then some leukemia cells are eliminated, but leukemia stem cells (LSCs) are not eliminated leading to treatment failure
Solution Approach 1:
The patent applies local quality by developing an antibody that specifically targets IL1RAP expression on leukemia stem cells rather than treating all cells uniformly. The antibody binds selectively to IL1RAP-positive LSCs, delivering a localized therapeutic effect that spares normal hematopoietic stem cells which do not express or express minimal levels of IL1RAP. This selective targeting resolves the contradiction by improving treatment effectiveness specifically against LSCs while maintaining reliability through differential expression exploitation.
Solution Approach 2:
The patent utilizes parameter changes by exploiting the differential expression level of IL1RAP between leukemia stem cells and normal hematopoietic stem cells. By designing an antibody that binds to IL1RAP with high affinity and selecting appropriate dosing parameters, the treatment achieves selective elimination of LSCs. The parameter of IL1RAP expression level serves as the distinguishing feature that enables selective targeting, thereby improving the ability to eliminate LSCs specifically.
2Reliability
If immunotherapy is used to target LSCs, then selective destruction of LSCs is achieved, but T-cell activation and cytotoxicity must be effectively induced
Solution Approach 1:
The patent applies the intermediary principle by using the anti-IL1RAP antibody as a mediator that bridges T-cells and leukemia stem cells. The antibody binds to IL1RAP on LSCs and simultaneously engages Fc receptors on T-cells, facilitating T-cell activation and cytotoxicity. This intermediary mechanism resolves the contradiction by enabling selective targeting of LSCs while effectively inducing T-cell mediated destruction through the antibody's dual binding capability.
Solution Approach 2:
The patent utilizes composite materials by creating a bispecific antibody that combines two different binding specificities: one for IL1RAP on LSCs and another for T-cell engaging ligands. This composite antibody structure integrates both targeting and effector activation functions into a single molecule, thereby achieving selective LSC targeting while simultaneously inducing potent T-cell cytotoxicity against the targeted cells.
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
The anti-IL1RAP antibody and recombinant proteins effectively induce T-cell activation and cytotoxicity in AML cells, demonstrating significant killing of leukemia cells while showing minimal toxicity to normal bone marrow cells, thereby potentially improving treatment outcomes for AML patients.
Implementation Method 1
anti-interleukin-1 receptor accessory protein (IL1RAP) antibody... target IL1RAP on leukemia cells
Implementation Method 2
induce T-cell activation and cytotoxicity in AML cells
Data Source
AI summary
Provided herein are, inter alia, antibodies capable of binding Interleukin-1 receptor accessory protein (IL1RAP). The antibodies provided herein include novel light chain and heavy chain sequences and bind IL1RAP with high efficiency and specificity. The anti-IL1RAP antibodies provided herein are, inter alia, useful for the treatment of IL1RAP-expressing cancers such as AML.