CD117 Aptamer-Methotrexate Conjugates for AML Therapy

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Solution Overview

Problem

Current treatments for acute myeloid leukemia (AML) are limited by adverse toxicities and lack of specificity, particularly for older patients, and there is a need for therapies that target CD117-expressing cells without affecting normal cells.

Innovation Solution

Development of an aptamer-agent conjugate comprising a nucleic acid aptamer that specifically interacts with CD117-expressing cells, conjugated with a therapeutic agent like methotrexate (Apt-MTX), which selectively targets and inhibits CD117-positive cells while sparing CD117-negative cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional chemotherapy is used to treat AML, then cancer cells are killed, but normal cells are also damaged causing severe toxicities

Engineering Contradiction:

Improvecancer cell killing effectivenessVSAvoidtoxicities to normal cells

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The chemotherapy approach is segmented into two distinct components: a targeting module (aptamer that specifically binds to CD117 on AML cells) and a therapeutic module (chemotherapeutic agent). This segmentation allows the drug to be delivered specifically to cancer cells while sparing normal cells, thereby maintaining cancer cell killing effectiveness while reducing toxicities to normal cells

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The aptamer acts as an intermediary molecule that mediates between the chemotherapeutic agent and the target cancer cells. It specifically recognizes and binds to CD117-expressing AML cells, delivering the chemotherapeutic agent directly to the cancer cells while preventing off-target effects on normal cells, thus resolving the contradiction between effectiveness and toxicity

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If standard chemotherapy is administered to older AML patients, then remission may be achieved, but life-threatening infections and cardiotoxicity occur

Engineering Contradiction:

Improveremission achievementVSAvoidlife-threatening infections and cardiotoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The therapy is divided into a targeting component (CD117-specific aptamer) and a therapeutic component (chemotherapeutic agent). This segmentation enables selective delivery of the chemotherapeutic agent to AML cells in older patients, achieving remission while avoiding the severe infections and cardiotoxicity that plague conventional chemotherapy in this vulnerable population

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The chemotherapeutic agent is delivered with local quality control through the aptamer's specific binding to CD117 on AML cells. This ensures high concentration of the drug at the target site (cancer cells) while maintaining low concentration in normal tissues, thereby achieving remission in older patients without causing life-threatening infections or cardiotoxicity

Inventive Principle:

Principle #3Local quality

3Adaptability or versatility

If non-specific chemotherapy is used, then treatment coverage is broad, but selectivity for CD117-expressing cells is lost

Engineering Contradiction:

Improvetreatment coverageVSAvoidselectivity for CD117-expressing cells

Core Design Contradiction:

Adaptability or versatilityVSMeasurement precision

Solution Approach 1:

The chemotherapy system is segmented into a universal therapeutic agent (maintaining broad treatment coverage) and a specific targeting module (aptamer that precisely recognizes CD117). This segmentation allows the chemotherapeutic agent to maintain its broad efficacy against cancer cells while the aptamer ensures high selectivity for CD117-expressing AML cells, resolving the contradiction between treatment coverage and selectivity

Inventive Principle:

Principle #1Segmentation

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 aptamer-agent conjugate effectively inhibits the growth of CD117-positive AML cells with minimal impact on normal cells, demonstrating targeted therapy with reduced side effects.

Implementation Method 1

a nucleic acid aptamer that specifically interacts with CD117-expressing cells

Methodology Applied

Scientific EffectMolecular recognition and binding:

Data Source

PatentUS10683506B2CD117 ligand-drug conjugates for targeted cancer therapy

Publication Date: 2020.06.16 THE METHODIST HOSPITAL

AI summary

Disclosed are compositions and methods relating to nucleic acid aptamers that specifically target CD117 protein and also selective binding to CD117-expressing cells. The ligand-drug conjugates specifically target CD117-expressing cells and subsequently internalize into the cells, leading apoptosis, growth inhibition, and death of cells of interest and no off-target toxicity to CD117-negative normal cells.