Induced Myeloid Suppressive Cell Production via Serum-Free Suspension Differentiation

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Solution Overview

Problem

Current methods for manufacturing immune regulatory cells, such as myeloid-derived suppressor cells (MDSCs), face challenges including paucity, heterogeneity, poor scalability, high cost, and reliance on serum-containing media and embryoid body formation, which hinders efficient and consistent production for adoptive cell therapies.

Innovation Solution

A method for producing clinically relevant numbers of induced immune regulatory cells, including MDSCs, using a medium composition with ROCK inhibitors, growth factors, and cytokines, which directs the differentiation of induced definitive hemogenic endothelium cells without the need for embryoid body formation or serum, enabling scalable and consistent production.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If embryoid body formation and serum-containing media are used for MDSC differentiation, then immune regulatory cells can be produced, but manufacturing scalability and consistency are poor

Engineering Contradiction:

Improvemanufacturing consistencyVSAvoidmanufacturing scalability

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The invention extracts and eliminates the embryoid body formation step from the differentiation protocol. By directly differentiating pluripotent stem cells into MDSCs without forming embryoid bodies, the method removes a source of heterogeneity and manual intervention, thereby improving manufacturing consistency and scalability.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention replaces expensive and variable serum-containing media with a defined, serum-free culture medium. This defined medium provides consistent nutrient and growth factor composition, eliminating batch-to-batch variability associated with serum and improving manufacturing reliability.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

2Productivity

If manual aggregation and embryoid body formation are employed, then cell differentiation can be initiated, but labor intensity increases and cell numbers minimally increase

Engineering Contradiction:

Improvecell number expansionVSAvoidlabor intensity

Core Design Contradiction:

ProductivityVSEase of manufacture

Solution Approach 1:

The invention enables pluripotent stem cells to automatically aggregate and form three-dimensional structures in suspension culture without manual intervention. The cells self-organize into compact spheres through natural adhesion mechanisms, eliminating the need for labor-intensive manual aggregation steps while maintaining differentiation efficiency.

Inventive Principle:

Principle #25Self-service

Solution Approach 2:

The invention performs cell aggregation and three-dimensional structure formation as a preliminary step that occurs automatically in suspension culture before differentiation is initiated. This preliminary self-organization prepares the cells for efficient differentiation and expansion without requiring subsequent manual manipulation.

Inventive Principle:

Principle #10Preliminary action

3Manufacturing precision

If embryoid bodies are maintained for 7-10 days for differentiation, then cellular maturation occurs, but manufacturing time and process complexity increase

Engineering Contradiction:

Improvecellular differentiation qualityVSAvoidmanufacturing cycle time

Core Design Contradiction:

Manufacturing precisionVSLoss of time

Solution Approach 1:

The invention inverts the traditional differentiation sequence by first forming three-dimensional cell structures in suspension and then initiating differentiation. This reversed approach allows differentiation to occur directly in the three-dimensional architecture, eliminating the need for prolonged embryoid body maintenance and subsequent transfer to adherent culture.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention merges the cell aggregation step and the differentiation step into a single continuous process. By initiating differentiation while cells are in suspension and forming three-dimensional structures, the method combines two previously separate operations, reducing total manufacturing time and process complexity.

Inventive Principle:

Principle #5Merging (Combining)

4Reliability

If EBs are transferred to adherent culture or dissociated for further maturation, then cell development continues, but process steps and manufacturing complexity greatly increase

Engineering Contradiction:

Improvemanufacturing reproducibilityVSAvoidprocess steps

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention creates a universal culture system where pluripotent stem cells can be differentiated into MDSCs entirely in suspension culture. This single culture mode serves multiple functions: cell aggregation, three-dimensional structure formation, and differentiation, eliminating the need for multiple culture system transitions and improving manufacturing reproducibility.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20240158747A1Composition and methods for inducing myeloid suppressive cells and use thereof

Publication Date: 2024.05.16 FATE THERAPEUTICS INC

AI summary

Compositions and methods for manufacturing induced immune regulatory cells comprising induced myeloid suppressive cells including MDSCs (myeloid-derived suppressor cells), dendritic cells, macrophages, and subpopulations thereof are provided. Also provided are methods and compositions for further modifying and modulating the induced immune regulatory cells to achieve enhanced therapeutic potential in treating autoimmune disorders, hematological malignancies, solid tumors, viral infections, neurodegenerative disorders, inflammatory conditions, or GvHD.