Multifunctional NK Cell Engager for Leukemia Treatment

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Solution Overview

Problem

There is an urgent need for effective treatment methods for patients with acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), and myelodysplastic syndromes (MDS) who are ineligible for or have exhausted standard therapeutic options.

Innovation Solution

The method involves administering a combination comprising a multifunctional binding protein with specific antigen binding domains for CD123 and NKp46, along with a BCL-2 inhibitor and/or a DNA hypomethylating agent, to treat or prevent leukemia and myelodysplastic syndromes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional chemotherapy is used to treat leukemia and myelodysplastic syndromes, then treatment can be provided to patients, but leukemic stem cells remain resistant and cause disease relapse

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidchemotherapy resistance

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent combines multiple therapeutic modalities into a single treatment regimen: a bispecific binding protein that simultaneously targets CD123 on leukemic cells and NKp46 on natural killer cells, combined with a BCL-2 inhibitor and a DNA hypomethylating agent. This combination approach addresses chemotherapy resistance by engaging both direct cytotoxic effects and immune-mediated destruction of leukemic stem cells.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The bispecific binding protein performs multiple functions: it acts as an immune checkpoint modulator by binding NKp46, as a targeted delivery vehicle by binding CD123, and as a bridge to recruit natural killer cells to the tumor site. This multi-functionality allows a single agent to address multiple aspects of leukemia pathogenesis and treatment resistance.

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Adaptability or versatility

If standard therapeutic options are exhausted, then patients have limited treatment alternatives, but effective treatment remains unavailable

Engineering Contradiction:

Improvetreatment optionsVSAvoidtreatment availability

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent employs a DNA hypomethylating agent to preliminarily modify the epigenetic state of leukemic cells, making them more susceptible to subsequent BCL-2 inhibition and bispecific protein-mediated cytotoxicity. This preliminary epigenetic modulation prepares the cells for enhanced response to the combination therapy, effectively creating a new treatment pathway for patients who have exhausted standard options.

Inventive Principle:

Principle #10Preliminary action

3Productivity

If a multifunctional binding protein targeting CD123 and NKp46 is administered, then target cell lysis increases, but treatment complexity increases

Engineering Contradiction:

Improvetarget cell lysisVSAvoidtreatment regimen

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent merges multiple therapeutic functions into a single bispecific binding protein molecule, which simultaneously engages CD123 on target cells and NKp46 on natural killer cells. This consolidation reduces the number of separate components that would otherwise be needed to achieve the same therapeutic effect, thereby managing treatment complexity while maintaining high productivity.

Inventive Principle:

Principle #5Merging (Combining)

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 results in an increased target cell lysis, providing a potential treatment option for patients who have limited alternatives, with the combination potentially leading to a several-fold increase in target cell lysis compared to using any component alone.

Implementation Method 1

a multifunctional binding protein comprising a first antigen binding domain (ABD) with binding specificity to CD123 (an antigen of interest on tumoral target cells) and a second (ABD) with binding specificity to NKp46 (a surface biomarker on immune NK cells)

Methodology Applied

Scientific EffectAntigen-antibody binding:

Data Source

PatentUS20250195653A1Multifunctional natural killer (NK) cell engager combination therapy for treating hematological neoplastic disorders

Publication Date: 2025.06.19 SANOFI SA(FR)

AI summary

The present disclosure relates to methods for treating or preventing a leukemia or a myelodysplastic syndrome in a subject in need thereof, said method comprising administering to the subject an effective amount of a combination comprising: (i) a binding protein comprising a first antigen binding domain (ABD) with binding specificity to CD123 and a second (ABD) with binding specificity to NKp46; and one or both of: (ii) a BCL-2 inhibitor, and (iii) a DNA hypomethylating agent.