Stem Cell Selection via HLA-Class I and CD46 Markers

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Solution Overview

Problem

Current allogeneic stem cell therapies face challenges with immunogenicity and suitability, particularly in presensitized patients and retreatment scenarios, due to immune responses against donor antigens, leading to potential rejection and reduced efficacy.

Innovation Solution

An in vitro method for selecting stem cell populations suitable for allogeneic therapy by culturing cells with IFN-γ to induce HLA-Class I expression, exposing them to varying concentrations of HLA-Class I antibodies, and assessing complement-dependent cytotoxicity to identify populations with reduced immunogenicity, specifically targeting a ratio of EC50 values and CD46 expression levels.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If allogeneic stem cell therapy is applied, then treatment availability and scalability are improved, but immunogenicity and rejection risk increase

Engineering Contradiction:

Improvetreatment availabilityVSAvoidimmunogenicity

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent applies preliminary action by pre-selecting stem cell populations with specific characteristics (low HLA-Class I expression, high CD46 expression) before transplantation. This pre-screening process identifies donor cells that are less likely to trigger immune rejection, allowing allogeneic therapy to proceed without requiring intensive post-transplant immunosuppression while maintaining treatment availability

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent employs parameter changes by modifying the selection criteria for stem cell donors based on specific molecular markers. By changing the focus from traditional HLA-matching to selecting for low HLA-Class I expression and high CD46 expression levels, the patent identifies cell populations that naturally resist complement-dependent cytotoxicity, thereby reducing immunogenicity while preserving the ability to provide allogeneic treatments

Inventive Principle:

Principle #35Parameter changes

2Measurement precision

If HLA-Class I expression is increased in stem cells, then immune recognition and rejection risk increase, but cell selection accuracy for presensitized patients improves

Engineering Contradiction:

Improvecell selection accuracyVSAvoidrejection risk

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

The patent applies inversion by reversing the traditional approach to HLA matching. Instead of selecting donors with high HLA-Class I expression to ensure immune recognition and compatibility, the patent selects for low HLA-Class I expression combined with high CD46 expression. This inverted selection strategy exploits the protective effect of CD46 against complement-mediated lysis, allowing accurate selection of cells that will survive in presensitized patients without triggering rejection

Inventive Principle:

Principle #13The other way round (Inversion)

3Reliability

If stem cell populations are selected for reduced immunogenicity, then treatment suitability for presensitized patients improves, but selection process complexity increases

Engineering Contradiction:

Improvetreatment suitabilityVSAvoidselection process complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent replaces complex mechanical or procedural matching systems with a molecular marker-based selection approach. By using flow cytometry or other detection methods to measure HLA-Class I and CD46 expression levels on donor cells, the patent simplifies the selection process into a standardized assay-based procedure. This substitution of the selection mechanism maintains high treatment suitability for presensitized patients while making the process more systematic and less complex than traditional HLA typing and matching protocols

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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 method enhances the suitability of stem cell populations for allogeneic therapy by reducing immunogenicity, thereby improving treatment outcomes in presensitized patients and during retreatment by selecting cells resistant to alloreactivity, mediated by increased CD46 expression.

Implementation Method 1

culturing a sample of an SC population in the presence of an IFN-γ concentration capable of inducing maximal HLA-Class I expression in said SC population

Methodology Applied

Scientific EffectInterferon-gamma signaling:

Implementation Method 2

contacting the test sample and the control sample with a range of different concentrations of an HLA-Class I antibody under conditions such that the HLA-Class I antibody binds to HLA-Class I expressed in the test sample and the control sample

Methodology Applied

Scientific EffectAntigen-antibody binding:

Implementation Method 3

adding complement to the test sample and the control sample such that the bound HLA-Class I antibody is saturated with complement and complement-dependent cytotoxicity (CDC) is induced

Methodology Applied

Scientific EffectComplement-dependent cytotoxicity:

Data Source

PatentUS20220202868A1Improved stem cell populations for allogeneic therapy

Publication Date: 2022.06.30 TAKEDA PHARMA CO LTD

AI summary

The present invention relates to an improved stem cell population for allogeneic stem cell therapy, in particular for the treatment of presensitized patients and for retreatment. Further, methods for obtaining said stem cell populations are provided. In addition, the present invention relates to pharmaceutical compositions comprising said stem cell populations and their use in allogeneic stem cell therapy.