Takara Bio broke news that the Medical Products Agency (“MPA”), the Swedish national authority responsible for regulation of drug and medical products, granted the company a manufacturing license for derivation and banking of human embryonic stem (hES) cells to be produced under GMP conditions. The cells will be produced at Takara Bio’s manufacturing laboratory located in Göteborg, Sweden, within Takara Bio Europe’s facility.
This announcement makes Takara Bio the first company worldwide to offer this service for human ESCs.
Takara Bio’s Role with Human Pluripotent Stem Cells
The significance of this event is that Takara Bio is now capable of providing a safe, reliable source of hES cells for future cellular therapeutic development by sourcing starting material from FDA-compliant facilities according to FDA guidelines and leveraging its proprietary, feeder-free hES cell establishment method, which is animal- and human-component free.
Historically, Takara Bio has had long-standing experience in human embryonic stem cell derivation, and under this new MPA license, it can offer this as a contract manufacturing service for customers who are focused on clinical cell therapy applications.
As summarized by Hiroki Tomohisa, CEO of Takara Bio Europe AB: “Takara Bio Europe’s long-standing experience in hES cell derivation is offered as a contract manufacturing service under the MPA license. We have a proprietary feeder-free hES cell establishment method which is animal- and human-component free. Starting material is retrieved from FDA-compliant sources according to FDA guidelines.”
Takara Bio’s Cell and Gene Therapy CDMO Business
Takara Bio’s basic strategy for the Gene Therapy segment is to develop and commercialize cutting edge technologies that are essential to gene therapy, by applying the technologies developed in their Bioindustry segment. In addition to their involvement in clinical trials, for more than four years, since the fall of 2014, Takara Bio has been offering cell and gene therapy manufacturing and operational support as a Contract Development and Manufacturing Organization (CDMO) business at the Center for Gene and Cell Processing, located in Kusatsu, Japan. A CDMO is a company that serves cell therapy companies on a contract basis. Common cell therapy CDMO services include cell therapy product development, manufacturing, clinical trial support, and commercial supply.
Although cell therapy manufacturing is becoming of mounting importance as growing numbers of cell therapeutics make their way through clinical trials, one of the major issues with moving cell therapy products from “bench to bedside” has been manufacturing bottlenecks. The heterogeneous nature of cell therapy products has introduced manufacturing complexity and regulatory concerns, as well as scale-up complexities that are not present within traditional pharmaceutical manufacturing.
Among cell therapy companies, the pressure for manufacturing innovation and optimization can incentivize them to seek third-party partners who possess technical, manufacturing, and regulatory expertise, such Takara Bio. According to Elizabeth Quinn, Associate Director, Stem Cell Marketing at Takara Bio USA, the goal of the Takara Bio is to provide “custom solutions that can address any stage of the gene and cell therapy development process.”
Clearly, Takara Bio’s Göteborg facility for derivation and banking of human embryonic stem (hES) cells to be produced under GMP conditions complements its global efforts to meet the needs of clients within the gene and cellular therapy industries.
Takara Bio’s Expertise in CAR-T
Takara Bio also has interesting expertise in the “hot” area of CAR-T. At first the trend was subtle, but CAR-T funding has been rapidly expanding as CAR-T therapies like Kymriah and Yescarta have reached the marketplace and created a CAR-T funding craze. In particular, CAR-T start-ups have been richly funded by investors eager to get into this trending area of regenerative medicine and IPO raises have also been aggressive.
Following IPOs by CAR-T players Kite Pharma, Bellicum, Juno and Cellectis totaling over $750 million, CAR-T developer Autolus announced a $150 million IPO in June 2018. This brought the total value of recent CAR-T IPOs to nearly $1 billion.
For over 20 years, Takara Bio has developed novel products with important gene therapy applications, positioning it to ride this wave of CAR-T enthusiasm. In 1995, Takara Bio and Indiana University developed the RetroNectin method, which involves using a plate-coating substance to increase the physical interactions of cells and viruses, greatly increasing transduction efficiency.
Since that time, the company has developed additional ways of using the RetroNectin method and viral vector technology for new therapeutic applications, such as in boosting naïve T-cell expansion for CAR-T therapy.
RetroNectin reagent, now available as a GMP-grade version, has been used in over 60 clinical studies around the world. In addition to integrating this product into its T-cell immunotherapy manufacturing service, Takara has also developed RetroNectin GMP Grade to support the needs of the clinical research community.
Takara Bio’s Relationship with Shinya Yamanaka and Kyoto University’s CiRA
A project at Takara Bio that captured my attention is the development of a quality-control system for maintaining a large stock of induced pluripotent stem (iPS) cells needed for clinical trials.
Kyoto University’s Center for iPS Cell Research and Application (CiRA), headed by Shinya Yamanaka, is collaborating with Takara Bio to ensure that the needs of iPS cell clinical research and therapeutic use are met.
The relationship with Shinya Yamanaka is significant, because he discovered iPS cells in mice in 2006 and derived them from humans in 2007. The partnership with CiRA is even more substantial, because CiRA is the premier institution promoting clinical research and studies with human iPS cells, most recently announcing that it is moving iPSC-derived platelets toward trials in humans with the goal to initiate clinical activity by 2019.
Takara Bio Group and the Cellartis Brand
The Takara Bio Group of companies has three primary sub-brands, which are: Takara, Clontech, and Cellartis. The Cellartis brand is of particular interest, because it is focused on stem cell-derived products and services for drug discovery, disease modeling, and regenerative medicine applications.
Historically, a key focus of the brand has been developing and distributing pluripotent stem cell lines, including both human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs).
Logically, Takara Bio’s recently launched clinical-grade hES cell production service is being offered under the Cellartis brand.
Recently, the Cellartis brand has been expanding its range of stem cell product applications. In one interesting example, it launched an iPS Cell to Hepatocyte Differentiation System, which allows researchers to easily generate hepatocytes from iPSCs on demand. In another intriguing example, it launched the Cellartis DEF-CS Culture System, a unique approach to culturing stem cells that offers significant advantages relative to other methods.
Takara Bio’s iPS Cell Differentiation Expertise
While I have traditionally thought of Takara Bio as a diversified provider of research tools, the company is increasingly starting to focus on stem cell research and clinical-grade solutions. Takara Bio now offers research use only (RUO) products and services for hepatocyte, definitive endoderm (DE), beta cell, and cardiomyocyte differentiation.
For hepatocytes, it has a complete portfolio including:
- Frozen iPS-derived hepatocyte kits from three normal donors
- “Do-it-yourself” hepatocyte differentiation kits which allows researchers to start from any human iPS or ES donor line and differentiate all the way to hepatocytes
- Customized services where its scientists will perform the hepatocyte differentiation on behalf of the customer
It also recently launched the Cellartis Human iPS and ES KnockIn and KnockOut Gene Editing Services. These services allow Takara Bio to combine its expertise in precise, footprint-free gene editing using CRISPR/Cas9 with its expertise in human pluripotent stem cell culturing and directed differentiation into hepatocytes, DE cells, beta cells and cardiomyocytes.
This enables the generation of disease models that are essential for advancing the understanding of disease mechanisms and the development of novel therapeutics.
Takara Bio’s Experience in Hepatocyte Differentiation
Takara Bio has also developed a standardized differentiation protocol for industrial scale production of iPS-derived hepatocytes that mimics embryonic development to yield pure cells that exhibit the functionality and characteristics of mature hepatocytes.
Its protocol results in pure, functional hepatocytes that are functionally mature and give low variability from batch-to-batch. To the best of my knowledge, Takara Bio is the first company offering a a standardized hepatic differentiation procedure that is generally applicable across a large panel of hPSC (iPS and ES) lines without any adaptations to individual lines.
By applying this “universal” protocol across hPSC-heps derived from different donor lines, one can mirror the metabolic diversity typically observed in human primary hepatocytes from different donors. Based on recent advances in iPSC technology, iPSC lines can now be derived from individuals with specific genotypes or phenotypes.
Combining this progress with Takara Bio’s DEF-CS culture system and robust hepatic differentiation protocol allows for the generation of homogenous hepatocyte cultures from customized panels of hiPSC lines at a large scale. It also opens up new possibilities for drug discovery, toxicology studies, and regenerative medicine applications.
Because of the universal nature of Takara Bio’s differentiation protocol, it commercialized a kit to allow researchers to differentiate their own iPS lines into DE cells or hepatocytes. For those who prefer the easy route, Takara will also do this as an outsourced service.
Finally, Takara Bio now provides batches of terminally differentiated hiPS-HEP cells from multiple donors to be used in drug screening and disease model applications.
Takara Bio’s Growing Role as a Stem Cell Solution Provider
When I dug a little deeper into the company’s catalogue, I also found that Takara Bio offers:
- DEF-CS 500 for culture of iPSCs in a monolayer – Monolayer culture enables single cell cloning after gene editing to generate clonal iPS lines that maintain pluripotency and have a stable karyotype.
- iPS-derived beta cells – Takara Bio has cells from two normal donors, as well as one (from ChiPSC22) with an HLA type that has a higher susceptibility to diabetes and is a useful model for diabetes and obesity disease model research.
- Power medium– Power medium is culture medium used to maintain human primary hepatocyte cultures for 4 weeks in culture. Although this is not a direct stem cell product, this is the same medium that is used in the company’s hiPS-HEPv2 kits and ithttps://www.takarabio.com/products/stem-cell-research/media-and-supplements/primary-hepatocyte-medium maintains the life of iPS-derived hepatocytes for 4 weeks in culture.
This hepatocyte long-term maintenance medium allows for more advanced functional studies to be performed, such as long-term toxicity studies.
A search of PubMed.gov revealed that several researchers are investigating the use of the Power medium for HBV infection studies that require hepatocytes to remain in culture for long periods of time.
Finally, Takara Bio offers:
- Human iPS and ES donor lines – Off-the-shelf hPS donor lines that are banked and characterized according to the highest industry standards and have proper donor consenting.
- Cellartis iPSC Single-Cell Cloning DEF-CS Culture Media Kit– A complete system for efficient expansion and scale-up manufacturing of hiPS cells in a feeder-free and defined environment. The kit contains all the necessary reagents to go from seeding single hiPS cells into 96-well plates to expansion of clones into 48-well plates.
- Cellartis iPSC rCas9 Electroporation (or Gesicle) and Single-Cell Cloning System– A complete system that allows efficient gene editing of hiPS cells via electroporation, followed by single-cell cloning and expansion into 48-well plates
The Future of Takara Bio?
Clearly, Takara Bio is establishing a growing foothold in the stem cell space, including the development of diverse capabilities around both human iPS cells and ESCs. As the first and only market research firm to specialize in the stem cell industry, we will be tracking this company’s product development pipeline with a keen eye.
Do you have questions about Takara Bio’s products or services? Ask them in the comments below.
Source/Sponsor: Takara Bio