Despite decades of research, treatment for many diseases still focuses on the management of symptoms. Regenerative medicine aims to use cell and gene therapy, and tissue engineering, to treat the root cause of disease by repairing, replacing, or regenerating tissues and metabolic processes. DC-Biotech, based in Kyoto, Japan, was created to accelerate the clinical development of regenerative medical products, particularly in cancer and osteoarthritis.
Building a regenerative medicine company
DC-Biotech was founded in 2021 as a personal response to a major area of unmet need. Members of the company’s co-founding team, Takahiro Mikami (an assistant professor at Showa University School of Medicine), Yoshiaki Saegusa (president and representative director of DC-Biotech), and Kazuhisa Inoue (CFO of DC-Biotech), had lived with knee osteoarthritis and issues with chronic pain, both of which are diseases treated by managing symptoms rather than tackling the underlying cause. After seeing significant differences in pain levels and mobility after the administration of autologous adipose-derived mesenchymal stem cells (AD-MSCs), the co-founders—graduates of the University of Tokyo—pooled funds to start DC-Biotech with the goal to expand the use of regenerative medicine, increase its accessibility across society, and extend healthy life expectancy.
As a first step, to create an income stream and to validate the science, DC-Biotech is establishing itself as a contract development and manufacturing organization (CDMO) in Japan, with plans to collaborate with partners in both Japan and other Asian countries including China and South Korea. Joint research projects to accelerate the clinical development of regenerative medical products are under way with a range of institutions, including the University of Tokyo Faculty of Veterinary Medicine, Kansai Medical University, and the Tsurumi University School of Dental Medicine. DC-Biotech’s services include manufacturing a range of cells for use in regenerative medicine and cancer therapy.
Natural killer (NK) cells can identify and attack abnormal cells. DC-Biotech selectively expands NK cells bearing the cluster of differentiation, CD16, membrane protein. The company cultures the NK cells producing over 1 billion in two weeks and over 5 billion in three weeks. The cells’ activity, including high cytotoxic response and interferon-γ secretion, can be maintained over three weeks of culture. Antibody-based cancer drugs such as Rituxan (rituximab) and Herceptin (trastuzumab) have been shown to enhance the antitumor effect of NK cells, and DC-Biotech’s NK cells have the potential to be used synergistically in combination with adoptive cell therapy (ACT).
DC-Biotech manufactures dendritic-cell vaccines from monocytes collected from blood in its quality-controlled manufacturing facility (Fig. 1). DC-Biotech’s dendritic cells use cancer-marker antigens including Wilms tumor protein (WT1), mucin-1 (MUC-1), and apoptosis inhibitor survivin (also known as baculoviral IAP repeat-containing protein 5 or BIRC5), as they are regarded as safe for human administration under Japan’s Act on the Safety of Regenerative Medicine.
Fig. 1 | Creating cells for the development of regenerative medicine products. In regenerative medicine, when using mesenchymal stem cells and immune cells such as CAR-T it is essential to overcome cellular senescence and exhaustion. The two compounds discovered by DC-BIOTECH hold the potential to address these challenges.
Natural killer T cells (NKT cells), which show characteristics of both NK cells and T cells, act as adjuvants in NK cell and T-cell therapy in cancer treatment. They can also influence the maturation of dendritic cells. DC-Biotech has developed NKT-cell-inducing dendritic cells using a patented method that it has called αNKT. The dendritic cells express the cell-surface protein CD1d, which binds to the company’s artificially synthesized glycolipids. The dendritic cells present the glycolipids to NKT cells, inducing them to exert their anti-tumor effects.
DC-Biotech produces MSCs derived from adipose tissue from abdominal liposuction, or from dental pulp from extracted teeth. Under a collaboration with the Tsurumi University School of Dental Medicine, DC-Biotech has established methods for isolating, culturing, preserving, and transporting MSCs derived from dental pulp. Basic research and exploratory clinical trials are underway for clinical applications.
“As we expand our CDMO business, we believe that building strong partnerships is essential across all phases, from technology development, through manufacturing to commercialization. In particular, we seek strategic alliances with organizations that excel in clinical trials and have a track record in international expansion so that we can create value together,” said Saegusa.
DC-Biotech takes a collaborative view on fundraising, looking for sponsors that have expertise and networks that can contribute to company growth.
“We especially value relationships with investors and venture capital firms who have deep knowledge in the healthcare sector and who can support our global expansion. Our goal is to achieve long-term, sustainable growth through such partnerships,” said Inoue.
Creating a technical platform
DC-Biotech’s technical platform is based on two low-molecular-weight compounds that were identified by its founding members in-house. Validation experiments were carried out between January and June 2023. These compounds have the potential to rejuvenate cells when added during the ex vivo culture of regenerative medical products, and may address key issues such as the decline in proliferation capacity during MSC passaging, and T-cell exhaustion in chimeric antigen receptor (CAR)-T cell production.
“When clients outsource cell manufacturing to our company, we aim to provide high-quality products using our proprietary technology,” said Mikami. “These small molecules could also have potential as standalone pharmaceuticals.”
An NKT-cell therapy for advanced cholangiocarcinoma that is unresponsive to standard treatment is being jointly researched with Kansai Medical University, while an autologous adipose-derived MSC therapy for knee osteoarthritis is being jointly developed with domestic hospitals.
Collaborative research
In 2024, DC-Biotech began working with Hirotaka Tomiyasu, an associate professor based in the Department of Veterinary Medical Sciences at the University of Tokyo. The joint research and development project aims to establish a tumor diagnostic method using blood-derived exosomes as biomarkers, by analyzing the molecular profiles of exosomes in the blood of tumor-bearing dogs. Tomiyasu has worked in this area for the last decade, including research on the role of extracellular vesicles in dogs with lymphoma, and how extracellular vesicles can change tumor phenotypes.
Diagnosing cancer in animals can be challenging as they can’t communicate their symptoms, so tumors are only found once they become advanced. Many companion animals can also disguise pain. Tomiyasu’s goal is to establish a precise and non-invasive test that could become part of routine health checks, similar to a prostate cancer test in humans.
Previous research hasn’t found any clinically useful biomarkers to differentiate canine cases with neoplastic diseases from those with non-neoplastic diseases, so Tomiyasu has developed an ultracentrifugation-based method to isolate extracellular vesicles from dogs with hemangiosarcoma, canine lymphoma, or mast-cell tumors. Tomiyasu has collected the extracellular vesicles derived from around 1.5 ml of peripheral bloods from 10 individual cases, and is now carrying out a comprehensive analysis, including protein profiles using liquid-chromatography tandem mass spectrometry (LC-MS/MS) and microRNA (miRNA) profiles using small RNA sequencing. Tomiyasu will then compare the profiles with samples from healthy dogs in order to find candidate biomarkers.
“It will be a long journey, but we have made an important first step,” said Tomiyasu. “Once the method has been validated in animals, our goal is to apply it to humans.”
In another project, DC-Biotech is working with Masaki Kaibori of Kansai Medical University, a professor and surgeon specializing in the surgical treatment of the liver and gallbladder. Advanced biliary tract cancer is hard to treat, with extremely poor outcomes. Immune checkpoint inhibitors have been used, but the response rates are as low as 20–30% and life expectancy is only six months to a year. Dendritic cell vaccines have potential, but the NKT cells induced by the vaccines can be inactivated by tumor immune checkpoints. Combining dendritic cell vaccines with immune checkpoint inhibitors may have potential, particularly in this type of cancer where there are few other options.
Kaibori has carried out a trial combining dendritic cell vaccines and immune checkpoint inhibitors in six patients with advanced biliary tract cancer. While results have not yet been finalized, initial analysis shows a response rate above 30%. A larger scale clinical study is planned, and the approach could have potential in other cancers.
“Our aim is to establish a better strategy for treating advanced biliary and liver cancers by combining cell therapy, immunotherapy, surgery, radiotherapy, and chemotherapy” said Kaibori.
Next steps for the company
DC-Biotech’s goal is to make regenerative medicine more accessible. Its plan is to get regulatory approval for regenerative medicine products, including NKT cells, MSCs, and mesenchymal stromal cells.
“Our first major milestone will be the expansion of the CDMO business across Asia, including Japan. In parallel, we aim to establish proof of evidence for the ex vivo application of our two small-molecule compounds, which will become a central strength of our company moving forward,” said Mikami.