Apparatus
Inventors
Ling, Jian • Zimmern, Kreg A. • Milone, Michael C.
Assignees
University of Pennsylvania Penn • Southwest Research Institute SwRI
Publication Number
US-12134757-B2
Publication Date
2024-11-05
Expiration Date
2040-05-12
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Abstract
Described herein is a beads-free bioprocessor as an automated and cost-effective T cell processing and manufacturing platform. T cells are a core component in CAR T cell therapies for cancer treatment, but are difficult to manufacture to scale in clinically relevant quantities. The 3D bioprocessor provides an alternative device that is scalable, beads-free, easy-to-use, and cost-effective for using CAR T cell therapy in cancer immunotherapy. Besides CAR T cell application, this platform technology has potential for many other applications such as cancer cell isolation.
Core Innovation
The invention provides a beads-free 3D bioprocessor apparatus designed as a cell processing and manufacturing platform, particularly aimed at automated and cost-effective T cell production. The apparatus comprises a plurality of spherical beads interconnected by rods, forming a fixed, layered structure with high surface-to-volume ratio. The structure is coated with a protein layer, to which one or more biotinylated antibodies are immobilized, allowing for selective activation, binding, or capture of targeted cells as the processing fluid passes through the device.
The problem addressed is the need for safer, cost-efficient, and scalable T-cell processing methods in CAR T cell therapies. Existing manufacturing processes rely on magnetic beads, require complex multistage handling, and are open systems prone to contamination, manual labor, and manufacturing failures, especially with certain patient populations. Furthermore, these methods increase costs, and the risk of non-T cell contamination introduces both safety and efficacy concerns.
By providing a scalable, closed, beads-free, and easily manufactured device compatible with a range of biocompatible materials, the 3D bioprocessor enables automated cell expansion, activation, separation, and purification. The structure supports efficient T cell activation and expansion, while also enabling isolation of other cell types by utilizing antibodies specific to the desired targets. The regular fixed mesh design ensures consistent interaction between cells and the coated surfaces, improving efficiency and reproducibility in cell processing applications.
Claims Coverage
The patent presents four independent claims that define key inventive features relating to the structure, surface coatings, antibody immobilization, and organization of the 3D bioprocessor apparatus.
Three-dimensional apparatus comprising spherical beads and rods in multi-layer offset structure with protein coating
An apparatus comprising: - A plurality of spherical beads and a plurality of rods interconnecting them - Spacing between adjacent beads provided by rods - Bead diameters from about 10 μm to about 10 mm - Rod lengths from about 0.1 μm to about 25 mm - Fixed organization in two or more layers, with each layer offset in x, y, and z directions from adjacent layers in a rotational fixed orientation - A protein coating present on the surface of the apparatus
Apparatus with layer-offset bead/rod structure and immobilized biotinylated antibodies on protein coating
An apparatus comprising: - A plurality of spherical beads and rods interconnecting the beads - Spacing provided between adjacent beads by the rods - Bead diameters from about 10 μm to about 10 mm - Rod lengths from about 0.1 μm to about 25 mm - Organization in two or more layers, each offset from adjacent layers - A protein coating on the surface of the apparatus - One or more biotinylated antibodies immobilized to the protein coating
Apparatus with beads and rods, fixed in rotational orientation and multi-layer offset, with protein coating
An apparatus comprising: - A plurality of spherical beads and rods interconnecting the beads - Spacing between adjacent beads provided by rods - Bead diameters from about 10 μm to about 25 mm - Rod lengths from about 0.1 μm to about 25 mm - Fixed organization in two or more layers, each layer offset in x, y, and z directions from adjacent layers, and in a rotational fixed orientation - A protein coating on the surface of the apparatus
Apparatus with repeatable fixed structure of beads and rods in multi-layer, rotationally fixed orientation and protein coating
An apparatus comprising: - A plurality of spherical beads and rods interconnecting the beads - Spacing between adjacent beads provided by rods - Bead diameters from about 10 μm to about 25 mm - Rod lengths from about 0.1 μm to about 25 mm - Fixed organization in a repeatable structure - Organization in two or more layers with each layer offset in x, y, and z directions from an adjacent layer and in a rotational fixed orientation - A protein coating on the surface of the apparatus
The independent claims define an apparatus with a unique multi-layered, rotationally fixed structure of interconnected beads and rods, functionalized with surface protein coating and, optionally, immobilized biotinylated antibodies. The inventive features enable customizable, scalable, and efficient cell processing, activation, and isolation.
Stated Advantages
Provides a low cost, easy to manufacture, easy-to-use, and single-use platform for cell processing in cell and gene therapy.
Achieves a high surface-to-volume ratio for increased reactivity between cells and the bioprocessor surfaces.
Prevents cellular uptake of the structure, overcoming disadvantages of microbead approaches by being larger and having a fixed structure.
Ensures uniform and repeatable structure for consistent bioprocessing and hydrodynamic forces on cells.
Reduces risk of contamination by providing a closed system compared to open, bead-based systems.
Facilitates scalability, flexibility, and ease of process scale-up, scale-down, and scale-out using 3D printing manufacturing.
Supports automation and minimizes manual labor, potentially reducing GMP compliance costs.
Allows precise control of shear stress and cell-surface interaction via adjustable perfusion flow parameters.
Documented Applications
Automated and cost-effective T cell processing and manufacturing, including expansion, activation, and harvesting of T cells for CAR T cell therapy.
Scalable cell platform for autologous and allogenic CAR-T cell therapies.
Cancer cell isolation, including isolation of rare cell types such as cancer cells using antibody-coated beads.
Cell separation, isolation, and purification of specific cell types (e.g., T cells, NK cells, B cells) from mixed cell populations.
Applications in cell and gene therapy manufacturing processes.
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