Polydonor CD4+ T Cells for GvHD Therapy
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Solution Overview
Problem
The production of donor-derived or autologous Tr1 cells for large-scale therapy in patients with high unmet medical needs is not feasible, cumbersome, and does not allow for the generation of large quantities of pure Tr1 cells.
Innovation Solution
A population of polydonor CD4IL-10 cells is developed, which are CD4+ T cells obtained from at least two different T cell donors and genetically modified to comprise an exogenous polynucleotide encoding IL-10. These cells are not alloantigen-specific and are used for therapeutic purposes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If donor-derived or autologous Tr1 cells are produced for large scale therapy, then immune suppression efficacy is improved, but production complexity and time increase significantly
Solution Approach 1:
The patent performs preliminary action by pre-isolating and expanding Tr1 cells from healthy donors before they are needed for therapy. These pre-prepared Tr1 cells can be stored and quickly administered when clinical need arises, eliminating the time-consuming process of generating Tr1 cells from patient-derived cells at the moment of treatment.
Solution Approach 2:
The patent uses healthy donor Tr1 cells as an intermediary solution. Instead of directly converting patient cells to Tr1 cells (which takes time), the invention mediates the process by using pre-generated Tr1 cells from healthy donors that can be transferred to patients, achieving the same therapeutic effect more efficiently.
2Reliability
If donor-derived or autologous Tr1 cells are produced for large scale therapy, then immune suppression efficacy is improved, but manufacturing complexity increases
Solution Approach 1:
The patent segments the complex manufacturing process into distinct phases: Tr1 cell isolation from healthy donors, expansion in culture, quality control testing, and storage. This segmentation allows each step to be optimized and standardized independently, reducing overall manufacturing complexity compared to generating Tr1 cells from patient cells at the point of care.
Solution Approach 2:
The patent changes key parameters by using healthy donor cells instead of patient cells, and by controlling culture conditions to optimize Tr1 cell expansion. These parameter changes simplify the manufacturing process by eliminating the need for complex patient-specific processing while maintaining therapeutic efficacy.
3Manufacturing precision
If single-donor CD4IL-10 cells are used, then batch consistency is improved, but production quantity is limited
Solution Approach 1:
The patent merges cells from multiple healthy donors to create a pooled Tr1 cell product. By combining Tr1 cells from several donors, the invention achieves both large production quantities and consistent batch characteristics, overcoming the limitation of single-donor preparations which cannot provide sufficient cell numbers for large-scale therapy.
4Productivity
If Tr1 cells are produced for large scale therapy, then therapeutic availability is improved, but cell purity decreases
Solution Approach 1:
The patent replaces complex mechanical separation methods with magnetic-activated cell sorting (MACS) technology. This substitution allows for rapid, large-scale purification of Tr1 cells from mixed cell populations while maintaining high purity levels, enabling both large production quantities and high cell purity to be achieved simultaneously.
Data Source
AI summary
The present disclosure provides a population of polydonor CD4IL-10 cells generated by genetically modifying CD4+ T cells from at least two different T cell donors. Further provided are methods of generating the polydonor CD4IL-10 cells and methods of using the polydonor CD4IL-10 cells for immune tolerization, treating GvHD, cell and organ transplantation, cancer, autoimmune and inflammatory diseases and other immune disorders.