Regulatory T Cell Lineage Stability via Subset Segmentation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current challenges in adoptive T cell therapy with regulatory T cells include the instability of T REG cells under inflammatory conditions, impurities of non-T REG effector T cells, and the difficulty in manufacturing pure T REG cell products.
Innovation Solution
A composition comprising CD4+CD25+CD127low regulatory T cells, enriched with naive, naive-like memory, and central memory regulatory T cell subsets, while excluding effector memory regulatory T cells, to enhance lineage stability and immunoregulatory potency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If bulk T REG cell populations are used for adoptive immunotherapy, then the manufacturing process is simpler, but the lineage stability under inflammatory conditions deteriorates
Solution Approach 1:
The patent segments the bulk T REG cell population into distinct subsets based on memory phenotype markers (CD45RA, CCR7, CD62L). It identifies and isolates specific subsets (naive T REG cells: CD45RA+CCR7+CD62L+; central memory T REG cells: CD45RO+CCR7+CD62L+) that demonstrate enhanced lineage stability. This segmentation allows selection of stable subsets while simplifying manufacturing by focusing on defined phenotypic criteria rather than complex functional assays.
Solution Approach 2:
The patent applies local quality by assigning different functional properties to different T REG cell subsets. Specifically, it identifies that naive and central memory T REG cell subsets possess superior lineage stability and immunoregulatory potency compared to effector memory subsets. By enriching for these specific subsets with defined phenotypic markers, the patent creates a product with localized enhanced quality in terms of stability and efficacy.
2Reliability
If T REG cell products are purified to high purity, then safety and efficacy are improved, but the manufacturing complexity increases
Solution Approach 1:
The patent performs preliminary action by pre-enriching T REG cells from peripheral blood mononuclear cells using magnetic beads conjugated to anti-CD25 antibodies before further subset selection. This preliminary purification step reduces the burden on subsequent subset enrichment steps and removes most non-T REG cells early in the manufacturing process, thereby improving safety while managing overall manufacturing complexity.
Solution Approach 2:
The patent replaces complex mechanical separation methods with antibody-based magnetic bead enrichment and flow cytometry-based sorting. These biochemical and optical methods provide higher purity and more precise subset isolation with simpler operational procedures compared to traditional mechanical cell separation techniques.
3Quantity of substance
If effector memory T REG cells are included in the product, then the cell yield is higher, but the immunoregulatory potency and stability deteriorate
Solution Approach 1:
The patent changes the phenotypic parameters used to define the T REG cell product by specifying memory status markers (CD45RA, CCR7, CD62L expression patterns). By defining the product in terms of naive and central memory phenotypes rather than total T REG cell count, the patent ensures enhanced immunoregulatory potency and lineage stability while accepting that cell yield may be reduced compared to including all T REG subsets.
Data Source
Figure 1A~1B
Figure 1C~1E
Figure 2A~2G
AI summary
The present invention relates to the field of immunotherapy, in particular, to adoptive T cell therapy with regulatory T cells. The invention provides a composition comprising CD4+CD25+CD127low regulatory T cells having an enhanced lineage stability to inflammatory triggers, as well as methods of preparing such compositions, as well as methods producing regulatory T cell products by expanding such compositions. Regulatory T cell products obtained according to the method of the invention can be used e.g., for treating a subject having or at risk of having an undesired immune response, such as a subject having an autoimmune disease, an allergy or other overwhelming inflammatory diseases, a transplant or a gene therapy recipient.