WO2020000532A1 - 基于机械臂的全自动细胞培养方法及其系统 - Google Patents

基于机械臂的全自动细胞培养方法及其系统 Download PDF

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Publication number
WO2020000532A1
WO2020000532A1 PCT/CN2018/096105 CN2018096105W WO2020000532A1 WO 2020000532 A1 WO2020000532 A1 WO 2020000532A1 CN 2018096105 W CN2018096105 W CN 2018096105W WO 2020000532 A1 WO2020000532 A1 WO 2020000532A1
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Prior art keywords
cells
culture
unit
cell culture
robotic arm
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PCT/CN2018/096105
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English (en)
French (fr)
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胡祥
刘沐芸
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深圳赛动生物自动化有限公司
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Priority to JP2019541071A priority Critical patent/JP2020528731A/ja
Priority to US16/527,008 priority patent/US20190390153A1/en
Publication of WO2020000532A1 publication Critical patent/WO2020000532A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4631—Chimeric Antigen Receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/464838—Viral antigens
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/34—Measuring or testing with condition measuring or sensing means, e.g. colony counters
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M3/00—Tissue, human, animal or plant cell, or virus culture apparatus
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M45/00—Means for pre-treatment of biological substances
    • C12M45/05—Means for pre-treatment of biological substances by centrifugation
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M47/00—Means for after-treatment of the produced biomass or of the fermentation or metabolic products, e.g. storage of biomass
    • C12M47/04—Cell isolation or sorting
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/10—Cells modified by introduction of foreign genetic material

Definitions

  • the present application relates to a cell culture method, and more particularly, to a robotic arm-based fully automatic cell culture method and system.
  • the existing manual semi-automatic equipment on the market is aimed at local process steps in the full production process, and can only be produced for a single patient within the same period of time, in order to achieve the scale of industrialized cell production and effectively reduce the production cost band
  • the benefits are limited.
  • the traditional manual cell culture method has the disadvantages of low efficiency, high probability of contamination, high error rate, and difficult quality control. Due to the different experience, methods and habits of operators, the cultured cell state is often inconsistent, making the culture process Poor reproducibility, stability, and uniformity, which affect the quality of cells. At present, the most reliable way is to use artificial systems instead of artificial culture. This has become the current industry trend.
  • the purpose of the present application is to overcome the shortcomings of the prior art and provide a fully automatic cell culture method based on a robotic arm and a system thereof.
  • a robotic arm-based full-automatic cell culture method the method includes:
  • a further technical solution thereof is: a step of processing another batch of T cells during the expansion culture and the expansion culture again, including the following specific steps:
  • a further technical solution thereof is: a step of performing culture processing on another batch of T cells, including performing T cell sorting, and / or, performing expansion culture on the sorted T cells, and / or, T cells after expansion and culture are CAR transfected, and / or T cells after CAR transfection are expanded and cultured again.
  • a further technical solution thereof is: a step of performing CAR transfection on the T cells after expansion and culture, including the following specific steps:
  • the present application also provides a robotic arm-based fully automatic cell culture system, including a sorting unit, a culture unit, a centrifugal transfection unit, and an acquisition unit; [0028] Wherein, the sorting unit is configured to sort T cells from raw blood;
  • the culture unit is configured to expand and culture the sorted T cells, and expand and culture the CAR-transfected T cells again;
  • the centrifugal transfection unit is used to perform CAR transfection on the T cells after expansion and culture;
  • the acquisition unit is configured to acquire the cultured CAR-T cells.
  • the system further includes an operation unit for operating cells in a sorting unit, a culture unit, a centrifugal transfection unit, and an acquisition unit, and the operation unit includes a six-degree-of-freedom GMP-compliant robot, a fixture And a dust-proof linear guide, a clamp is connected to the six-degree-of-freedom GMP-compliant robot, and the six-degree-of-freedom GMP-compliant robot is disposed on the dust-proof linear guide.
  • the culture unit includes a CO 2 incubator and a culture bag storage module.
  • the centrifugal transfection unit includes a centrifuge.
  • the obtaining unit includes a detection module, a discharging module and a waste storage module
  • the detection module is configured to collect and detect basic quality data on the obtained cells
  • the discharging module is used for discharging the finished product
  • the waste storage module is configured to store used consumables and medicaments.
  • the system further comprises an environmental control unit
  • the environment control unit is configured to control the sorting unit, the culture unit, the centrifugal transfection unit, and the obtaining unit in a compliant and sterile environment of GMP.
  • the beneficial effects of the present application compared with the prior art are:
  • the robotic arm-based full-automatic cell culture method of the present application uses the robotic arm to run the cells in various stages of cell culture, and expands and regenerates cells.
  • another batch of T cells is processed, and during the process of culturing another batch of cells, another batch of cells can be interspersed to improve the efficiency of cell culture, and save the cost of preparation.
  • Centrifuge transfection and collection culture The subsequent cells are also executed automatically to achieve fully-automatic cell culture and improve the efficiency of cell culture.
  • FIG. 1 is a first flowchart of a robotic arm-based fully automatic cell culture method provided by a specific embodiment of the present application
  • FIG. 2 is a second flowchart of a robotic arm-based fully automatic cell culture method provided by a specific embodiment of the present application
  • FIG. 3 is a specific flowchart of processing another batch of T cells during expansion culture and re-expansion culture provided by a specific embodiment of the present application;
  • FIG. 4 is a detailed flowchart of CAR transfection of T cells after expansion and culture provided by a specific embodiment of the present application
  • FIG. 5 is a structural block diagram of a robotic arm-based fully automatic cell culture system provided by a specific embodiment of the present application
  • FIG. 6 is a structural block diagram of an obtaining unit provided by a specific embodiment of the present application.
  • the robotic arm-based full-automatic cell culture method provided in this embodiment can be used to culture various cells such as red blood cells, to achieve fully-automatic cell culture, and to re-culture In the process of one cell, another cell can be interspersed and cultured to improve the efficiency of cell culture and save the cost of preparation.
  • this embodiment provides a fully automatic cell culture method based on a robotic arm.
  • the method includes
  • the above steps S6 to S7 are based on the operation of the raw blood and the cells in each link according to the robotic arm. [0062] For the above SI step, specifically, obtaining the raw blood of the cells to be cultured, such as the raw blood of a patient.
  • T cell sorting is performed on the raw blood, specifically, batch density cells are separated by density gradient centrifugation, the separated cells are washed, the washed cells are sampled and counted, and OKT3 is added. Adjust the density, perform cell seeding, and complete cell sorting.
  • the step of performing CAR transfection on the expanded and cultured T cells includes the following specific steps:
  • steps S3 to S4 it is necessary to perform the following steps: sampling the inoculated cells to calculate the number and survival rate, and taking photos to save them; dividing according to the number; adding IL-2 and culture medium; and preparing cells in culture carry out testing.
  • step S6 the step of processing another batch of T cells during the expansion culture and the expansion culture again includes the following specific steps:
  • S62 Perform culture processing on another batch of T cells.
  • the liquid distribution tank is set as two independent and separated spaces, or two liquid distribution tanks with the same functions are provided.
  • the two tanks are independent of each other, can be sterilized independently, and do not interfere with each other, and can realize cell culture in different batches.
  • Fast switching between batches ensures that there is no interference and cross-contamination between batches; in order to achieve the multi-batch and multi-patient cell culture at the same time, it greatly improves production efficiency and reduces costs under the premise of conforming to GMP.
  • the step of performing a culture process on another batch of T cells includes performing T cell sorting, and / or, performing expansion culture on the sorted T cells, and / or, T cells after expansion and culture are CAR transfected, and / or T cells after CAR transfection are expanded and cultured again.
  • step S62 the batch of T cells will be transferred to the next step of the culture environment with the assistance of a robotic arm for rapid culture, that is, regardless of that For a batch of cell culture, the above-mentioned steps S1 to S7 must be completed, and the difference lies in which batch of cell expansion culture is the current cell interspersed or in the process of expansion culture again.
  • step S7 specifically: obtaining cells in a new culture bag; washing the cells; The washed cells are sampled and counted; the counted cells are tested at the factory; the cells that meet the factory test are stored frozen and stored in the sampling tube.
  • the robot simulates various process operations of various cell cultures manually, completes cell separation and sorting, Infection, liquid manipulation, cultivation, collection, frozen storage packaging and other processes, while supporting the quality detection module 41 in the production process, can automatically complete the relevant central control project detection.
  • Integrated environmental control module Each cabin is sealed independently to form a Class A space that is completely isolated from the background environment.
  • the equipment can be installed and operated in the lowest clean class: Class D environment.
  • the system corresponding to this method can be flexibly installed in hospitals, clinics, biological service companies, and pharmaceutical factory buildings, and is highly adaptable to the environment.
  • the system also integrates a space sterilization system to meet the sterilization needs of different production processes. The sterilization process can be repeatedly verified and meets GMP requirements.
  • the robotic arm automatically runs the cells in each culture process to achieve automatic culture of the cells.
  • the cost of equipment purchase, plant and facility construction and consumables purchase is not higher than the traditional manual method, the operating cost is greatly reduced; the interference caused by human and environmental factors during the production process is eliminated, and the stability of the cell preparation process is effectively improved And reproducibility, thereby effectively improving the uniformity and stability of product quality; effectively avoiding human operation errors, reducing the risk of core preparation intellectual property leakage due to personnel flow, and greatly reducing the high amount of repeated personnel training Cost; using the expansion and culture steps in the cell culture process, interspersing another batch of cell culture, and multiple batches of simultaneous preparation, greatly improving the efficiency of cell preparation, saving preparation costs, thereby accelerating the promotion and popularization of cell therapy, and benefiting the majority of patients .
  • this embodiment further provides a robotic arm-based fully automatic cell culture system, which includes a sorting unit 1, a culture unit 2, a centrifugal transfection unit 3, and an acquisition unit 4.
  • the sorting unit 1 is configured to sort T cells from the raw blood
  • a culture unit 2 for expanding and culturing the sorted T cells, and expanding and culturing the T cells after CAR transfection
  • a centrifugal transfection unit 3 configured to perform CAR transfection of T cells after expansion and culture
  • An acquisition unit 4 is configured to acquire the cultured CAR-T cells.
  • the above-mentioned system further includes an operation unit 5 for operating the cells in the sorting unit 1, the culture unit 2, the centrifugal transfection unit 3, and the acquisition unit 4.
  • the operation unit 5 includes a six-degree-of-freedom GMP-compliant robot, a jig And a dust-proof linear guide, a clamp is connected to the six-degree-of-freedom GMP compliant robot, and the six-degree-of-freedom GM P-compliant robot is disposed on the dust-proof linear guide.
  • the operation unit 5 performs the transfer of patient cell samples, preparation consumables, etc. between different working modules, and participates in process operations such as adding liquid.
  • the robot simulates various process operations of manual cell culture, completes cell separation and sorting, Infection, liquid manipulation, cultivation, collection, frozen storage packaging and other processes, while supporting the quality detection module 41 in the production process, can automatically complete the relevant central control project detection.
  • Integrated environmental control module Each cabin is sealed independently to form a Class A space that is completely isolated from the background environment.
  • the equipment can be installed and operated in the lowest clean class: Class D environment.
  • the system corresponding to this method can be flexibly installed in hospitals, clinics, biological service companies, and pharmaceutical factory buildings, and is highly adaptable to the environment.
  • the system also integrates a space sterilization system to meet the sterilization needs of different production processes. The sterilization process can be repeatedly verified and meets GMP requirements.
  • the robotic arm automatically runs the cells in each culture process to achieve automatic culture of the cells.
  • the cost of equipment purchase, plant and facility construction and consumables purchase is not higher than the traditional manual method, the operating cost is greatly reduced; the interference caused by human and environmental factors during the production process is eliminated, and the stability of the cell preparation process is effectively improved And reproducibility, thereby effectively improving the uniformity and stability of product quality; effectively avoiding human operation errors, reducing the risk of core preparation intellectual property leakage due to personnel flow, and greatly reducing the high amount of repeated personnel training Cost; using the expansion and culture steps in the cell culture process, interspersing another batch of cell culture, and multiple batches of simultaneous preparation, greatly improving the efficiency of cell preparation, saving preparation costs, thereby accelerating the promotion and popularization of cell therapy, and benefiting the majority of patients .
  • the culture unit 2 includes CO 2
  • Incubator and bag storage module When culturing cells, they need to be cultured in a (: 0 2 incubator).
  • the above-mentioned centrifugal transfection unit 3 includes a centrifuge, and performs operations such as virus (centrifugation) transfection and cell harvesting.
  • the above-mentioned obtaining unit 4 includes a detection module 41, a discharging module 42, and a waste storage module 44.
  • the detection module 41 is configured to collect and detect basic quality data on the obtained cells. It includes an automatic inverted microscope, a flow cytometer, and an optical cytometer. Collection of basic quality data during preparation, such as detection of total number of cells, cell proliferation rate, cell viability, transfection rate, cell subsets, etc.
  • the discharging module 42 is used for discharging the finished product.
  • a waste storage module 44 is configured to store used consumables and medicaments.
  • system further includes an environmental control unit 6.
  • An environmental control unit 6 is used to control the sorting unit 1, the culture unit 2, the centrifugal transfection unit 3, and the acquisition unit 4 in a GMP-compliant aseptic environment.
  • the environment control unit 6 comprises separate compartments each module and laminar flow sterilization module H 2 0 2.
  • the system is integrated with environmental control. Each cabin is sealed independently to form a class A dynamic laminar flow space.
  • the equipment can be installed and operated in a class D environment.
  • the system can be flexibly installed in hospitals, clinics, biological service companies, and pharmaceutical enterprise buildings. Highly adaptable.
  • the system also integrates a sterilization and disinfection system to meet the sterilization and disinfection needs of different production processes.
  • the above-mentioned system further includes a liquid operation unit 7.
  • the liquid operation unit 7 includes a bag / bottle liquid operation module, a large-capacity reagent solution operation module, and a small-capacity high-precision
  • the liquid operation module, the bottle opening / closing module, and the magnet operation module, and the liquid operation unit 77 are used to perform liquid operations with different capacities and different accuracy requirements in each process step.
  • the system also includes a refrigerator set including three temperature levels of -80 ° C, -20 ° C, and 4 ° C to provide environments such as low temperature storage.
  • the system further includes an electric control unit 8.
  • the electric control unit 8 includes a high-performance industrial computing server, a PLC control module, various types of sensor networks, and a power supply module, etc., and provides power for each unit.
  • the system further includes a storage unit 9 for temporarily storing materials used in the production process in the system.
  • the system also includes units such as data collection, quality management, and remote customer service, adapting to the traditional production center production model, while creating a new distributed cell preparation production model, providing direct services close to the end user, and providing different production and business models. Highly adaptable.
  • the robotic arm-based fully automatic cell culture system described above uses cells to operate on cells In the various stages of culture, during the expansion culture and the re-amplification culture, another batch of T cells is processed, and during the process of culturing another batch of cells, another batch of cells can be interspersed to improve the efficiency of cell culture. Moreover, the preparation cost is saved, and the use of centrifugal transfection and collection of cultured cells is also automatically performed to realize fully-automatic culture of cells and improve the efficiency of cell culture.

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Abstract

本申请公开了基于机械臂的全自动细胞培养方法及其系统，该方法包括获取原血；对原血进行T细胞分选；对分选后的T细胞进行扩增培养；对扩增培养后的T细胞进行CAR转染；对CAR转染后的T细胞再次扩增培养；在扩增培养以及再次扩增培养期间，对另一批T细胞进行处理；获取培养后的CAR-T细胞。

Description

基于机械臂的全自动细胞培养方法及其系统
[0001] 本申请是以申请号为 201810666385.3、 申请日为 2018年 6月 26日的中国专利申请 为基础， 并主张其优先权， 该申请的全部内容在此作为整体引入本申请中。
[0002] 技术领域
[0003] 本申请涉及细胞培养方法， 更具体地说是指基于机械臂的全自动细胞培养方法 及其系统。
[0004] 背景技术
[0005] 细胞疗法正引领未来医学革命。 细胞疗法成为继蛋白药物、 化学药物、 医药器 械之后的第四大类医疗方法， 而细胞治疗中， 细胞培养的工艺则是支撑细胞疗 法的根基， 但是目前传统的细胞培养工艺还存在以下不足：
[0006] 市场上现有的人工操作半自动化设备， 针对全生产流程中的局部工艺步骤， 且同一时段内只能为单个病人进行生产制备， 为实现工业化细胞生产规模及有 效降低制备生产成本带来的效益有限。 传统手工培养细胞的方式存在着效率低 、 受污染几率高、 出错率高、 质量监控难等弊端， 由于操作人员的经验、 手法 和习惯不同， 往往会导致所培养的细胞状态不一致， 使培养过程重现性、 稳定 性、 均匀一性差， 从而影响细胞的质量， 目前最可靠的途径就是使用自动化系 统来替代人工培养， 这已经成为当前行业的趋势， 在细胞应用需求迎来爆发性 增长的同时， 对提高细胞生产制备效率， 有效降低生产制备成本， 统一生产制 备质量标准等方面提出了更严苛的要求， 以满足巨大的市场容量及精准医疗中 多样性的需求。
[0007] 目前市场上有一些自动化的单体设备， 只能完成细胞培养工艺中某一步或某一 段操作， 仍需要靠人员将整个生产工艺串联起来， 而无法实现全流程自动化。 且目前细胞培养的操作环境通常为 C级背景下的局部开放式 A级， 或 B级背景下 局部开放式 A级， 这种传统的设计在 GMP合规上存在诸多弊端， 且厂房的硬件投 入、 后期的维护成本都很高， 从而导致细胞治疗的成本居高不下。
[0008] 因此， 有必要设计一种新的细胞培养方法， 实现全自动培养细胞， 且再培养一 批细胞的过程中， 可以穿插培养另一批细胞， 提高细胞培养的效率， 且节约制 备成本。
[0009] 申请内容
[0010] 本申请的目的在于克服现有技术的缺陷， 提供基于机械臂的全自动细胞培养方 法及其系统。
[0011] 为实现上述目的， 本申请采用以下技术方案： 基于机械臂的全自动细胞培养方 法， 所述方法包括：
[0012] 获取原血；
[0013] 对原血进行 T细胞分选；
[0014] 对分选后的 T细胞进行扩增培养；
[0015] 对扩增培养后的 T细胞进行 CAR转染；
[0016] 对 CAR转染后的 T细胞再次扩增培养；
[0017] 在扩增培养以及再次扩增培养期间， 对另一批 T细胞进行处理；
[0018] 获取培养后的 CAR-T细胞。
[0019] 其进一步技术方案为： 在扩增培养以及再次扩增培养期间， 对另一批 T细胞进 行处理的步骤， 包括以下具体步骤：
[0020] 对配液仓进行灭菌；
[0021] 对另一批次 T细胞进行培养处理。
[0022] 其进一步技术方案为： 对另一批次 T细胞进行培养处理的步骤， 包括进行 T细胞 分选， 和 /或， 对分选后的 T细胞进行扩增培养， 和 /或， 对扩增培养后的 T细胞进 行 CAR转染， 和 /或， 对 CAR转染后的 T细胞再次扩增培养。
[0023] 其进一步技术方案为： 对扩增培养后的 T细胞进行 CAR转染的步骤， 包括以下 具体步骤：
[0024] 往空包装袋中加入病毒培养若干个小时；
[0025] 把血液移入包装袋内， 培养若干个小时；
[0026] 对包装袋内物质进行清洗， 并转入新培养袋内。
[0027] 本申请还提供了基于机械臂的全自动细胞培养系统， 包括分选单元、 培养单元 、 离心转染单元以及获取单元； [0028] 其中， 所述分选单元， 用于对原血进行 T细胞分选；
[0029] 所述培养单元， 用于对分选后的 T细胞进行扩增培养， 对 CAR转染后的 T细胞 再次扩增培养；
[0030] 所述离心转染单元， 用于对扩增培养后的 T细胞进行 CAR转染；
[0031] 所述获取单元， 用于获取培养后的 CAR-T细胞。
[0032] 其进一步技术方案为： 所述系统还包括用于将细胞运转于分选单元、 培养单元 、 离心转染单元以及获取单元的运转单元， 运转单元包括六自由度 GMP合规机 器人、 夹具以及防尘直线导轨， 夹具与所述六自由度 GMP合规机器人连接， 所 述六自由度 GMP合规机器人设置于所述防尘直线导轨上。
[0033] 其进一步技术方案为： 所述培养单元包括 CO 2培养箱以及培养袋存储模块。
[0034] 其进一步技术方案为： 所述离心转染单元包括离心机。
[0035] 其进一步技术方案为： 述获取单元包括检测模块、 出料模块以及废料存储模块
[0036] 所述检测模块， 用于对获取的细胞进行基本质量数据的采集和检测；
[0037] 所述出料模块， 用于制成品的出料；
[0038] 所述废料存储模块， 用于存储已用耗材以及药剂。
[0039] 其进一步技术方案为： 所述系统还包括环境控制单元；
[0040] 所述环境控制单元， 用于控制分选单元、 培养单元、 离心转染单元以及获取单 元处于 GMP的合规无菌环境。
[0041] 本申请与现有技术相比的有益效果是： 本申请的基于机械臂的全自动细胞培养 方法， 通过利用机械臂将细胞运转于细胞培养的各个环节中， 在扩增培养以及 再次扩增培养期间， 对另一批 T细胞进行处理， 且再培养一批细胞的过程中， 可 以穿插培养另一批细胞， 提高细胞培养的效率， 且节约制备成本， 利用离心转 染以及收集培养后的细胞也是自动执行的， 实现全自动培养细胞， 提高细胞培 养的效率。
[0042] 下面结合附图和具体实施例对本申请作进一步描述。
[0043] 附图说明
[0044] 图 1为本申请具体实施例提供的基于机械臂的全自动细胞培养方法的流程图一 [0045] 图 2为本申请具体实施例提供的基于机械臂的全自动细胞培养方法的流程图二
[0046] 图 3为本申请具体实施例提供的在扩增培养以及再次扩增培养期间对另一批 T细 胞进行处理的具体流程图；
[0047] 图 4为本申请具体实施例提供的对扩增培养后的 T细胞进行 CAR转染的具体流程 图；
[0048] 图 5为本申请具体实施例提供的基于机械臂的全自动细胞培养系统的结构框图
[0049] 图 6为本申请具体实施例提供的获取单元的结构框图。
[0050] 具体实施方式
[0051] 为了更充分理解本申请的技术内容， 下面结合具体实施例对本申请的技术方案 进一步介绍和说明， 但不局限于此。
[0052] 如图 1〜 6所示的具体实施例， 本实施例提供的基于机械臂的全自动细胞培养方 法， 可以运用在培养血红细胞等各种细胞， 实现全自动培养细胞， 且再培养一 个细胞的过程中， 可以穿插培养另一个细胞， 提高细胞培养的效率， 且节约制 备成本。
[0053] 如图 1所示， 本实施例提供了基于机械臂的全自动细胞培养方法， 该方法包括
[0054] 51、 获取原血；
[0055] 52、 对原血进行 T细胞分选；
[0056] 53、 对分选后的 T细胞进行扩增培养；
[0057] 54、 对扩增培养后的 T细胞进行 CAR转染；
[0058] 55、 对 CAR转染后的 T细胞再次扩增培养；
[0059] 56、 在扩增培养以及再次扩增培养期间， 对另一批 T细胞进行处理；
[0060] 57、 获取培养后的 CAR-T细胞。
[0061] 上述的 S6步骤至 S7步骤， 具体是依据机械臂将原血以及细胞运转于各个环节中 [0062] 对于上述的 SI步骤， 具体是获取需要培养细胞的原血， 比如病人的原血等。
[0063] 对于上述的 S2步骤， 对原血进行 T细胞分选， 具体是对批量细胞采用密度梯度 离心法进行分离， 对分离后的细胞进行清洗， 对清洗后的细胞进行取样计数， 加入 OKT3， 调整密度， 进行细胞接种， 完成细胞的分选。
[0064] 更进一步地， 在某些实施例中， 对于上述的 S4步骤， 对扩增培养后的 T细胞进 行 CAR转染的步骤， 包括以下具体步骤：
[0065] S41、 往空包装袋中加入病毒培养若干个小时；
[0066] S42、 把血液移入包装袋内， 培养若干个小时；
[0067] S43、 对包装袋内物质进行清洗， 并转入新培养袋内。
[0068] 对于上述的 S3步骤至 S4步骤， 需要进行： 对接种的细胞进行取样计算数量以及 存活率， 拍照保存； 根据数量进行分装； 加入 IL-2和培养基； 对培养制备中的细 胞进行测试。
[0069] 对于上述的 S6步骤， 在扩增培养以及再次扩增培养期间， 对另一批 T细胞进行 处理的步骤， 包括以下具体步骤：
[0070] S61、 对配液仓进行灭菌；
[0071] S62、 对另一批次 T细胞进行培养处理。
[0072] 将配液仓设置为两个独立分开的空间， 或者设置两个功能完全相同的配液仓， 两个仓相互独立， 可单独灭菌， 互不干扰， 可实现不同批次细胞培养之间的快 速切换， 确保批次之间互不干扰和交叉污染； 以实现多批次、 多病人细胞同时 培养， 在符合 GMP的前提下大大提高了生产效率、 降低成本。
[0073] 对于上述的 S62步骤， 对另一批次 T细胞进行培养处理的步骤， 包括进行 T细胞 分选， 和 /或， 对分选后的 T细胞进行扩增培养， 和 /或， 对扩增培养后的 T细胞进 行 CAR转染， 和 /或， 对 CAR转染后的 T细胞再次扩增培养。
[0074] 如图 2所示， 在进行 S62步骤后， 该批次的 T细胞会在机械臂的协助下， 转运至 下一步骤的培养环境中， 以此进行快速培养， 也就是不管是那一批次的细胞培 养， 都必须完成上述的 S1步骤至 S7步骤的培养工序， 区别在于当前细胞穿插于 哪一批次的细胞扩增培养还是再次扩增培养过程中。
[0075] 对于上述的 S7步骤， 具体是： 获取新培养袋内的细胞； 对细胞进行清洗； 对清 洗后的细胞进行取样计数； 对计数后的细胞进行出厂测试； 将满足出厂测试的 细胞冷冻存储以及存储于取样管内。
[0076] 基于高自由度的机器人 （机械臂） 而设计， 集成通用的细胞制备 /质检设备， 机器人 （机械臂） 模拟人工进行各项细胞培养的各项工艺操作， 完成细胞分离 分选、 感染、 液体操作、 培养、 收集、 冻存封装等工艺， 同时配套生产过程中 的质量检测模块 41， 可自动完成相关中控项目的检测。 集成环境控制模块， 各 舱室独立密封形成与背景环境完全隔离的 A级空间， 设备可安装运行在最低洁净 级别： D级环境中。 该方法所对应的系统可灵活安装在医院、 诊所、 生物服务公 司、 制药企业厂房中， 对环境有高度的适应性。 系统中同时集成空间灭菌系统 ， 适应不同生产工艺的灭菌需求， 灭菌工艺可被重复验证， 符合 GMP要求。
[0077] 机械臂将细胞自动运转于各个培养过程中， 实现自动培养细胞。 在保持设备采 购、 厂房设施建设与耗材采购等费用不高于传统手工方法的前提下， 大大降低 运营成本； 排除制备生产过程中人为及环境因素带来的干扰， 有效提高细胞制 备工艺的稳定性和重现性， 从而有效提高产品质量的均一性、 稳定性； 有效避 免的人为操作错误， 降低因人员流动带来的核心制备知识产权的泄露风险， 大 幅度降低重复人员培训带来的高额成本； 利用细胞培养过程中扩增培养步骤， 穿插另一批细胞的培养， 多批次同步制备， 大大提高了细胞制备效率、 节约制 备成本， 从而加速细胞治疗的推广与普及， 使广大患者受益。
[0078] 上述的基于机械臂的全自动细胞培养方法， 通过利用机械臂将细胞运转于细胞 培养的各个环节中， 在扩增培养以及再次扩增培养期间， 对另一批 T细胞进行处 理， 且再培养一批细胞的过程中， 可以穿插培养另一批细胞， 提高细胞培养的 效率， 且节约制备成本， 利用离心转染以及收集培养后的细胞也是自动执行的 ， 实现全自动培养细胞， 提高细胞培养的效率。
[0079] 如图 5所示， 本实施例还提供了基于机械臂的全自动细胞培养系统， 其包括分 选单元 1、 培养单元 2、 离心转染单元 3以及获取单元 4。
[0080] 其中， 分选单元 1， 用于对原血进行 T细胞分选；
[0081] 培养单元 2， 用于对分选后的 T细胞进行扩增培养， 对 CAR转染后的 T细胞再次 扩增培养； [0082] 离心转染单元 3 , 用于对扩增培养后的 T细胞进行 CAR转染；
[0083] 获取单元 4， 用于获取培养后的 CAR-T细胞。
[0084] 上述的系统还包括用于将细胞运转于分选单元 1、 培养单元 2、 离心转染单元 3 以及获取单元 4的运转单元 5， 运转单元 5包括六自由度 GMP合规机器人、 夹具以 及防尘直线导轨， 夹具与所述六自由度 GMP合规机器人连接， 所述六自由度 GM P合规机器人设置于所述防尘直线导轨上。
[0085] 该运转单元 5执行病人细胞样本、 制剂耗材等在不同工作模块间的转运， 并参 与加液等工艺操作。
[0086] 基于高自由度的机器人 （机械臂） 而设计， 集成通用的细胞制备 /质检设备， 机器人 （机械臂） 模拟人工进行各项细胞培养的各项工艺操作， 完成细胞分离 分选、 感染、 液体操作、 培养、 收集、 冻存封装等工艺， 同时配套生产过程中 的质量检测模块 41， 可自动完成相关中控项目的检测。 集成环境控制模块， 各 舱室独立密封形成与背景环境完全隔离的 A级空间， 设备可安装运行在最低洁净 级别： D级环境中。 该方法所对应的系统可灵活安装在医院、 诊所、 生物服务公 司、 制药企业厂房中， 对环境有高度的适应性。 系统中同时集成空间灭菌系统 ， 适应不同生产工艺的灭菌需求， 灭菌工艺可被重复验证， 符合 GMP要求。
[0087] 机械臂将细胞自动运转于各个培养过程中， 实现自动培养细胞。 在保持设备采 购、 厂房设施建设与耗材采购等费用不高于传统手工方法的前提下， 大大降低 运营成本； 排除制备生产过程中人为及环境因素带来的干扰， 有效提高细胞制 备工艺的稳定性和重现性， 从而有效提高产品质量的均一性、 稳定性； 有效避 免的人为操作错误， 降低因人员流动带来的核心制备知识产权的泄露风险， 大 幅度降低重复人员培训带来的高额成本； 利用细胞培养过程中扩增培养步骤， 穿插另一批细胞的培养， 多批次同步制备， 大大提高了细胞制备效率、 节约制 备成本， 从而加速细胞治疗的推广与普及， 使广大患者受益。
[0088] 另外， 培养单元 2包括 C0 2
培养箱以及培养袋存储模块。 细胞培养时， 需要在（：0 2培养箱内培养。
[0089] 另外， 上述的离心转染单元 3包括离心机， 执行病毒 （离心） 转染、 细胞收获 等操作。 [0090] 更进一步地， 在某些实施例中， 上述的获取单元 4包括检测模块 41、 出料模块 4 2以及废料存储模块 44。
[0091] 检测模块 41， 用于对获取的细胞进行基本质量数据的采集和检测。 其包含自动 倒置显微镜、 流式细胞仪以及光学细胞仪。 执行制备过程中基本质量数据的采 集， 如细胞总数、 细胞增殖率、 细胞活率、 转染率、 细胞亚群等的检测。
[0092] 出料模块 42， 用于制成品的出料。
[0093] 废料存储模块 44， 用于存储已用耗材以及药剂。
[0094] 另外， 系统还包括环境控制单元 6。
[0095] 环境控制单元 6 , 用于控制分选单元 1、 培养单元 2、 离心转染单元 3以及获取单 元 4处于 GMP的合规无菌环境。
[0096] 该环境控制单元 6包括各舱室独立的层流模块以及 H 20 2灭菌模块。 系统中集成 环境控制， 各舱室独立密封形成 A级动态层流空间， 设备可安装运行在 D级环境 中， 该系统可灵活安装在医院、 诊所、 生物服务公司、 制药企业厂房中， 对环 境有高度的适应性。 系统中同时集成灭菌消毒系统， 适应不同生产工艺的灭菌 消毒需求。
[0097] 另外， 作为优选的实施例， 上述的系统还包括液体操作单元 7 , 具体地， 该液 体操作单元 7包括分袋 /分瓶液体操作模块、 大容量试剂溶液操作模块、 小容量高 精度液体操作模块、 开关瓶模块以及磁体操作模块， 液体操作单元 77用于执行 各工艺步骤中不同容量、 不同精度要求的液体操作。
[0098] 系统还包括包含 -80°C、 -20°C、 4°C三个温度等级的冰箱组， 以提供低温保存等 环境。
[0099] 系统还包括电控单元 8， 具体地， 电控单元 8包含高性能工业计算服务器、 PLC 控制模组、 各类型传感器网络以及电源模组等， 为各个单元提供电源。
[0100] 另外， 系统还包括储存单元 9 , 该储存单元 9用于生产过程中用到的物料的系统 内暂存。 系统还包括数据收集、 质量管理以及远端客户服务等单元， 适应传统 的制备中心生产模式， 同时创造全新的分布式细胞制备生产模式， 贴近终端用 户提供直接服务， 对不同的生产模式与商业模式有高度的适应性。
[0101] 上述的基于机械臂的全自动细胞培养系统， 通过利用机械臂将细胞运转于细胞 培养的各个环节中， 在扩增培养以及再次扩增培养期间， 对另一批 T细胞进行处 理， 且再培养一批细胞的过程中， 可以穿插培养另一批细胞， 提高细胞培养的 效率， 且节约制备成本， 利用离心转染以及收集培养后的细胞也是自动执行的 ， 实现全自动培养细胞， 提高细胞培养的效率。
[0102] 上述仅以实施例来进一步说明本申请的技术内容， 以便于读者更容易理解， 但 不代表本申请的实施方式仅限于此， 任何依本申请所做的技术延伸或再创造， 均受本申请的保护。 本申请的保护范围以权利要求书为准。
发明概述
技术问题
问题的解决方案
发明的有益效果

Claims

权利要求书
[权利要求 1] 基于机械臂的全自动细胞培养方法， 其特征在于， 所述方法包括： 获取原血；
对原血进行 T细胞分选；
对分选后的 T细胞进行扩增培养；
对扩增培养后的 T细胞进行 CAR转染；
对 CAR转染后的 T细胞再次扩增培养；
在扩增培养以及再次扩增培养期间， 对另一批 T细胞进行处理； 获取培养后的 CAR-T细胞。
[权利要求 2] 根据权利要求 1所述的基于机械臂的全自动细胞培养方法， 其特征在 于， 在扩增培养以及再次扩增培养期间， 对另一批 T细胞进行处理的 步骤， 包括以下具体步骤：
对配液仓进行灭菌；
对另一批次 T细胞进行培养处理。
[权利要求 3] 根据权利要求 2所述的基于机械臂的全自动细胞培养方法， 其特征在 于， 对另一批次 T细胞进行培养处理的步骤， 包括进行 T细胞分选， 和 /或， 对分选后的 T细胞进行扩增培养， 和 /或， 对扩增培养后的 T细 胞进行 CAR转染， 和 /或， 对 CAR转染后的 T细胞再次扩增培养。
[权利要求 4] 根据权利要求 3所述的基于机械臂的全自动细胞培养方法， 其特征在 于， 对扩增培养后的 T细胞进行 CAR转染的步骤， 包括以下具体步骤 往空包装袋中加入病毒培养若干个小时；
把血液移入包装袋内， 培养若干个小时；
对包装袋内物质进行清洗， 并转入新培养袋内。
[权利要求 5] 基于机械臂的全自动细胞培养系统， 其特征在于， 包括分选单元、 培 养单元、 离心转染单元以及获取单元；
其中， 所述分选单元， 用于对原血进行 T细胞分选；
所述培养单元， 用于对分选后的 T细胞进行扩增培养， 对 CAR转染后 的 T细胞再次扩增培养；
所述离心转染单元， 用于对扩增培养后的 T细胞进行 CAR转染； 所述获取单元， 用于获取培养后的 CAR-T细胞。
[权利要求 6] 根据权利要求 5所述的基于机械臂的全自动细胞培养系统， 其特征在 于， 所述系统还包括用于将细胞运转于分选单元、 培养单元、 离心转 染单元以及获取单元的运转单元， 运转单元包括六自由度 GMP合规 机器人、 夹具以及防尘直线导轨， 夹具与所述六自由度 GMP合规机 器人连接， 所述六自由度 GMP合规机器人设置于所述防尘直线导轨 上。
[权利要求 7] 根据权利要求 6所述的基于机械臂的全自动细胞培养系统， 其特征在 于， 所述培养单元包括（：0 2培养箱以及培养袋存储模块。
[权利要求 8] 根据权利要求 7所述的基于机械臂的全自动细胞培养系统， 其特征在 于， 所述离心转染单元包括离心机。
[权利要求 9] 根据权利要求 8所述的基于机械臂的全自动细胞培养系统， 其特征在 于， 述获取单元包括检测模块、 出料模块以及废料存储模块； 所述检测模块， 用于对获取的细胞进行基本质量数据的采集和检测； 所述出料模块， 用于制成品的出料；
所述废料存储模块， 用于存储已用耗材以及药剂。
[权利要求 10] 根据权利要求 9所述的基于机械臂的全自动细胞培养系统， 其特征在 于， 所述系统还包括环境控制单元；
所述环境控制单元， 用于控制分选单元、 培养单元、 离心转染单元以 及获取单元处于 GMP的合规无菌环境。
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