Guojian Chengnuo Receives China's First IND Approval for "Off-the-Shelf" Allogeneic CAR-NK Cell Injection Targeting Solid Tumors

On November 11, 2021, the Center for Drug Evaluation of China's National Medical Products Administration approved the clinical trial application for "Mesothelin (Mesothelin, MSLN) Chimeric Antigen Receptor NK Cell (CAR-NK) Injection" (referred to as: CAR-NK Injection), developed by Guojian Chengnuo Biotechnology (Beijing) Co., Ltd. (hereinafter referred to as Guojian Chengnuo), for the treatment of advanced epithelial ovarian cancer.

This product is the first domestically produced "off-the-shelf" allogeneic CAR-NK product to be formally approved by the National Medical Products Administration, marking a new milestone in the research of immune cell drug treatments for solid tumors.

In China, ovarian cancer is the second largest tumor in gynecology, but its mortality rate ranks first.

Currently, there are approximately 53,000 ovarian cancer patients in China, of which about 70% have epithelial tumors, meaning the number of epithelial cell cancer cases is around 37,000. Early diagnosis of ovarian cancer is difficult, and about 70% of patients are diagnosed at an advanced stage.

Although cytoreductive surgery and platinum-based combination chemotherapy are effective for patients with advanced ovarian cancer, the overall treatment outcomes remain poor, with a 5-year survival rate for stage III-IV ovarian cancer of only 30-40%. On the other hand, while cytoreductive surgery and platinum-based postoperative chemotherapy have extended patient survival, most patients experience severe chemotherapy-related side effects, and approximately 60% of patients relapse after receiving first-line chemotherapy.

For this significant and difficult-to-treat disease, there are currently no effective drugs available for treatment. The situation has been stagnant for 60 years without new breakthroughs, leaving patients' clinical needs unmet, with poor prognosis and high recurrence rates.

Therefore, there is an urgent need in clinical practice to explore new treatment methods for ovarian cancer to improve therapeutic outcomes and enhance patients' quality of life.

In response to the growing demand from patients, the Guojian Chengnuo team independently developed an anti-MSLN CAR-NK cell injection for ovarian cancer, marking the first CAR-NK product in China to be approved for IND. This product utilizes the NK cell's endogenous gene CD244 as the CAR structural backbone, which helps enhance the cytotoxicity of CAR-NK cells while preventing overactivation and extending their half-life. This innovative structure achieves superior tumor cell killing effects.

Dr. Hong Liu, General Manager of Guojian Chengnuo, stated: "Cell therapy primarily based on CAR-NK offers numerous advantages in cancer treatment."

"First, CAR-NK cells have the activity of rapidly killing tumors. Experiments found that the killing effect of CAR-NK cells can be observed in 1 hour in vitro and 4 hours in vivo; Secondly, when CAR-NK cells kill tumors, they do not produce cytokine storms, with low side effects, and their short retention time in vivo means no memory cells will appear."

"Moreover, CAR-NK cells can be infused allogeneically without causing graft-versus-host disease (GvHD); most importantly, the CAR-NK cell development by China's Guojian Chengnuo is based on automated intelligent manufacturing, creating 'off-the-shelf' products that enable standardized mass production, expand treatment opportunities, reduce treatment costs, and offer high clinical accessibility."

The company Guojian Chengnuo mentioned above is a biopharmaceutical enterprise focused on the research and industrial application of "off-the-shelf" CAR-NK cell new drugs for the treatment of solid tumors from various sources.

Guojian Chengnuo currently owns six major technology platforms: CAR-NK R&D platform, antibody screening platform, iPSC technology development platform, genetic testing platform, intelligent manufacturing production platform, and exosome development platform.

1.CAR-NK R&D PlatformFocusing on CAR-NK Technology Research and Industrialization. Guojian Chengnuo currently possesses comprehensive production and quality control processes for plasmids, lentiviruses, and retroviruses; it has independently developed technologies related to NK cell in vitro expansion and CAR-NK cell production, enabling the rapid acquisition of CAR-NK cells with high purity, high CAR positivity rates, and high yield; additionally, Guojian Chengnuo also holds diverse CAR structure modification technologies, which can continuously optimize the cytotoxic function of CAR-NK cells and expand their clinical indications.

2. Antibody Screening PlatformCan provide basic support for the research and development of cellular drugs. Guojian Chengnuo has established a large-capacity fully human natural phage antibody library and a mouse-derived immune phage antibody library, possesses a complete set of antibody screening, expression, purification, and validation technologies, and has the ability to enhance and modify known antibodies. Currently, Guojian Chengnuo has successfully screened high-affinity antibodies targeting various tumor antigens.

3.iPSC Technology Development PlatformIt can provide an adequate source of cells and address issues such as insufficient expansion of primary cells, low gene insertion efficiency, and high production costs. Through gene-editing technology, Guojian Chengnuo has successfully inserted various functional genes into the genome of iPSCs, induced differentiation into NK cells, and established a comprehensive quality control system. Guojian Chengnuo possesses iPSC production technology from different cell sources; through gene-editing technology, they have successfully inserted various functional genes into the iPSC genome. Currently, they have successfully induced iPSC differentiation into NK cells and completed the establishment of a quality evaluation system at the genetic and molecular levels.

4.Illumina Sequencing PlatformBased on this platform, Guojian Chengnuo independently developed gene detection and sequencing analysis products, which can help understand potential health risks through genetic information, plan personalized health management, and prevent major diseases in advance.

5. Intelligent Manufacturing Production PlatformBy integrating biotechnology, engineering technology, and information technology, a fully automatic intelligent cell culture system can be designed and manufactured, incorporating core patented technologies such as high-ratio cell expansion/transfection. This platform enhances production efficiency, shortens the production cycle, and boosts output to help companies lead the industry. Additionally, it utilizes an intelligent comprehensive testing platform to improve testing standards and ensure high product quality.

6. Exosome Application Development PlatformBased on MSC and IPSC, a complete standard operating procedure for exosome production and downstream concentration purification has been established, and multiple exosome detection methods have been independently developed. Meanwhile, through genetic engineering technology, various modifications of exosomes have been completed to enhance their targeting and drug-loading capabilities.

Six-in-one platform, synchronously supporting the R&D of new cell therapy drugs.

Guojian Chengnuo has multiple CAR-NK products under development based on these six platforms., respectively collaborating with domestic and international institutions and experts on preclinical development and IIT trials, with indications including ovarian cancer, non-small cell lung cancer, liver cancer, breast cancer, etc.

Dr. Hong Liu, Chairman & General Manager of Guojian Chengnuo, and has served as a reviewer for the National Natural Science Foundation, standing director of the Henan Pharmacological Society, editorial board member of "Chinese Pharmacist," and recipient of the "Innovation Talent Project for Higher Education Institutions in Henan Province," among other social positions. The main research focus is on cellular drug development. Led the application and completion of over 20 scientific projects including those from the National Natural Science Foundation and provincial major science and technology special projects, published more than 30 papers, obtained 3 national invention patents, and established 2 provincial-level scientific platforms.

Randy W. Schekman, the scientific advisor of Guojian Chengnuo, is also a notable figure., He is the 2013 Nobel Prize in Physiology or Medicine laureate and a member of the National Academy of Sciences., currently a professor in the Department of Molecular and Cell Biology at the University of California, Berkeley, and also a researcher at the Howard Hughes Medical Institute, primarily leading the team in studying the mechanisms of novel cellular drugs.

In addition, other core members of Guojian Chengnuo have rich industry experience in new drug registration, process development, quality management, preclinical research, and clinical trial design, forming a complete and complementary senior management structure.

Led by its core members, Guojian Chengnuo has set its main focus on the emerging field of CAR-NK therapy within the cell and gene therapy (CGT) sector. This area has also attracted major pharmaceutical giants such as Fate, Takeda, Sanofi, BMS, Cellectis, Cytovia, and Merck to actively invest. In 2020, the global transaction volume related to CAR-NK exceeded 30 billion yuan, with the current fastest progress reaching Phase I clinical trials.

Attracting numerous giants to lay out naturally has its unique advantages. NK cells possess multiple cytotoxic killing mechanisms, such as mediating immune responses by regulating other immune cells, antibody-dependent cell-mediated cytotoxicity (ADCC), apoptosis mediated by secreting lytic granules, and TNF-mediated cytotoxicity, all of which can kill tumor cells.

CAR-NK therapy based on this has the advantages of extensive cell sources, good safety, and scalability for mass production.

Currently, Guojian Chengnuo has obtained the underlying technology patents for CAR structure, CAR-NK cells, and their preparation methods.

Currently, the core product of Guojian Chengnuo, an anti-MSLN CAR-NK injection, has received IND approval from the National Medical Products Administration. This is also the first "off-the-shelf" allogeneic CAR-NK product approved by the CDE in China, marking an important milestone in the immunotherapy of solid tumors.

Targeting MSLN CAR-NK Cell Therapy Product Demonstrates Clear Tumor Suppression in Human Ovarian Cancer OVCAR8-luc Intraperitoneal Xenograft Models. According to the data, the therapeutic effect of targeting MSLN CAR-NK injection is superior to carboplatin, a first-line chemotherapy drug for ovarian cancer in clinical practice, effectively reducing tumor burden and significantly prolonging the survival of tumor-bearing mice.

The products are complemented by a range of intelligent cell production and testing equipment developed by Guojian Chengnuo., which can help the company scale up the production of CAR-NK products, and plans to sell them externally as a new revenue growth point for Guojian Chengnuo. Currently, one of Guojian Chengnuo's devices has applied for a Class II certificate, and another device is planned to apply for a Class III certificate. The GMP production workshop for instruments and equipment is also under construction simultaneously and is expected to be completed and put into operation by the end of the year.

Guojian Chengnuo has also planned a life science park of approximately 50,000 square meters within the Langfang Smart Cell Valley.The Science Park will be built into a cell and gene therapy-focused industrial park, including corporate headquarters, R&D centers, GMP workshops, small animal facilities, P3-level virology laboratories, testing and inspection centers, and academician workstations, providing comprehensive support for Guojian Chengnuo from research to production. The production line planning includes 3 plasmid lines, 5 virus lines, and 30 cell lines.

The rapid development of the industry cannot be separated from financial support. Guojian Chengnuo is also undergoing a new round of financing, which will be used for subsequent workshop construction, pipeline development, and Phase II clinical trials of core products.

In the future, we look forward to biopharmaceutical companies, including Guojian Chengnuo, developing more innovative drugs in the field of solid tumors, and writing a new chapter for life and health.