Shihe Biotech Advances Allogeneic Cancer Immunotherapy with High-Purity, High-Specificity Expanded NK Cell Product

The human immune system has three lines of defense. The first line is the external barrier composed of the skin and mucous membranes; the second line is innate immunity, consisting of bactericidal substances in body fluids and phagocytes; and the third line is adaptive immunity, comprising immune organs and immune cells. For diseases such as cancer, which arise from pathological changes in the body’s own cells, innate immunity serves as the body’s first line of defense against cancer.

Natural Killer (NK) cells are among the most critical immune cells in innate immunity, capable of eliminating virus-infected or cancerous cells, thereby playing a pivotal role in the body’s defense against various diseases. Unlike adaptive immunity mediated by T and B cells, which rely on coordinated interactions, NK cell activity is independent and not restricted by the Major Histocompatibility Complex (MHC). In simple terms, these cells do not require specific recruitment by the adaptive immune system, nor do they need cooperation from other cells or antibodies. Upon encountering abnormal cells, NK cells can independently recognize and attack them through non-specific mechanisms, exhibiting potent cytotoxicity.

In cancer treatment, in addition to the widely discussed CAR-T therapy, adoptive immunotherapy using natural killer (NK) cells is another highly promising approach. This potential stems not only from the potent cytotoxic activity of NK cells but also from their unique characteristic of being unrestricted by major histocompatibility complex (MHC) molecules. As allogeneic NK cells do not trigger an immune response in the recipient, off-the-shelf NK cell products can be administered directly for adjunctive anticancer therapy without the need for genetic engineering or patient pretreatment with immunosuppressive drugs.

Recent research findings have revealed that NK cells can also assist various antibodies in performing specific anti-cancer therapies, thereby enhancing therapeutic efficacy and playing a crucial role in immune checkpoint inhibitor treatment. Given the numerous advantages of NK cells in cancer therapy, the development of NK cell-based products has emerged as a highly competitive field.

However, the preparation of NK cells requires a stable manufacturing process, as the purity of NK cell products directly impacts the efficacy of subsequent NK cell-assisted therapies. Currently, most NK cell products on the market have a purity of approximately 70%. Beijing Shihe Biotechnology Co., Ltd. (hereinafter referred to as “Shihe Biotech”) has achieved the production of high-purity human NK cell injection (hpNK) through process upgrades. According to Dr. Cheng Yuan, General Manager of the company, the purity of Shihe Biotech’s NK cell products can now exceed 90%.

MHC is the key molecule by which T cells distinguish self from non-self, while cunning cancer cells have learned to evade T cell attacks by downregulating MHC expression. As a major component of the innate immune system, natural killer (NK) cells identify targets through “non-self” or “missing-self” recognition. Even if invasive microbes lack surface MHC, virus-infected host cells exhibit low levels of MHC on their surface, and tumor cells downregulate MHC; all of these conditions trigger NK cell-mediated attack.

In addition to their innate ability to kill tumor cells, the Fc receptors (FcR) on the surface of NK cells can bind to the Fc fragment of antibodies, thereby directing the killing of infected or tumor cells that are specifically recognized by the Fab fragment of the antibodies. This process is known as antibody-dependent cell-mediated cytotoxicity (ADCC).

Currently, clinical trials are underway evaluating NK cells in combination with numerous ADCC-enhancing tumor-targeting monoclonal antibodies, including rituximab (MabThera/Rituxan), trastuzumab (Herceptin), and cetuximab (Erbitux). NK cells can also be combined with immunomodulatory monoclonal antibodies (anti-PD-1/anti-PD-L1) to improve the efficacy of these agents.

Shihe Bio has secured multiple patents for the highly specific expansion of human NK cells, enabling the production of high-purity human NK cell products that outperform comparable domestic and international technologies and products across various technical indicators. The company has abandoned gene transduction and transfection methods for NK cell processing, opting instead for protein factor regulation to manipulate the cells, thereby yielding NK cells with enhanced vitality.

As a major component of the innate immune system, natural killer (NK) cells also serve as a potent complement to adaptive immunity. The high-purity human NK cell injection (hpNK) provided by Shihe Bio can act as a salvage therapy for first- and second-line treatment regimens, thereby benefiting a broader patient population.

Dr. Cheng Yuan told VCBeat that the primary objective proposed by Shihe Biotech for development was to maximize the purity of NK cells in the final product. Leveraging its understanding of NK cell development and growth, as well as its research on other cellular components present in the starting materials, Shihe Biotech conducted Design of Experiments (DOE) to evaluate multiple factors. Based on practical application considerations, the company selected optimal parameters and ultimately standardized the manufacturing process for NK cell preparation.

Shihe Biologics’ hpNK cell technology has been fully validated, featuring highly specific expansion without the need for magnetic bead selection. The process is simple and straightforward, eliminating coating and washing steps, and is free of serum, animal-derived components, and feeder cells. The resulting NK cells exhibit a purity of >90% and viability of >95%, with an expansion fold of 400–1,000 times, yielding a total cell count of 3×10⁹ to 1×10¹⁰. This facilitates analysis and ensures safe usage.

Shihe Bio’s NK cells maintain a lifecycle consistent with that of normal somatic cells, ensuring natural apoptosis within one to three months. Compared with international medical companies also engaged in primary NK cell therapy, Shihe Bio demonstrates superior technical indicators, including higher NK cell purity, a simpler manufacturing process, and standardized production that results in more competitive pricing. Although other domestic companies obtain NK cells through alternative methods, Shihe Bio distinguishes itself with more comprehensive basic research and preclinical data, a feeder-layer-free culture technology, and a higher CD16+ ratio.

Currently, Shihe Biotech has initiated clinical studies on the application of NK cells in liver diseases, combining them with immune checkpoint monoclonal antibodies (anti-PD-1/anti-PD-L1) for the treatment of liver cancer. Safety has been demonstrated, and efficacy data are currently being collected.

Dr. Cheng Yuan holds a Ph.D. in Biochemistry and Molecular Biology from the Institute of Biophysics, Chinese Academy of Sciences. He subsequently conducted postdoctoral research at Memorial Sloan Kettering Cancer Center (MSKCC). Dr. Cheng has served as General Manager at several healthcare companies, including Bo Hou Medical and Anmeijie Biotechnology. He has also held positions as Senior Scientist at Life Technologies and Chief Operating Officer at Sotio in the Czech Republic. Currently, Dr. Cheng serves concurrently as General Manager and Chief Scientist at Shihe Biotechnology.

Dr. Cheng Yuan, General Manager and Chief Scientist of Shihe Biotech

Dr. Hu Tianhui, Scientific Advisor to the Shihe Bio team, is a Professor at the School of Medicine, Xiamen University, with extensive experience in the diagnosis, treatment, and clinical research of intestinal tumors. Dr. Hu’s research focuses on two main areas: first, elucidating the specific molecular mechanisms underlying the initiation, progression, invasion, and metastasis of gastrointestinal tumors; and second, developing novel diagnostic reagents and therapeutic agents for colorectal cancer. Additionally, he seeks to identify early diagnostic biomarkers for gastrointestinal tumors at the genetic and protein levels, thereby providing new perspectives and methodologies for their diagnosis.

“New therapeutic drugs and treatment regimens are continually emerging, significantly improving outcomes for certain difficult-to-treat cancers. Nevertheless, substantial unmet needs remain,” stated Dr. Cheng Yuan. “Shihe Biotech focuses on targeted therapy and combination therapy. Its multi-targeted ADCC (antibody-dependent cellular cytotoxicity) agent demonstrates clear pharmacological efficacy, allows for earlier intervention, and has a broad range of applications. It holds promise as a salvage and adjunctive therapy to first- and second-line treatment regimens.”

The company will continue to leverage its advantages in cytokine-induced differentiation technology to develop somatic cell products with low application risks, and explore new combination therapy regimens, aiming to address the current challenges posed by the tumor microenvironment. Dr. Cheng Yuan revealed that the company will soon initiate an investigator-initiated trial (IIT) at a leading cancer hospital in Beijing, and has already launched two clinical studies in Jinan.

It is reported that Shihe Biotech has launched a new round of financing, aiming to raise RMB 10 million to 30 million. The proceeds will be primarily used to advance two clinical research projects under the company.