TianGang Immunopharma: Pioneering First-in-Class NK Cell-Targeted Cancer Immunotherapies

Tian Zhigang (left) guiding the R&D team.

■Reporters Wang Min and Shen Chunlei from China

Natural Killer Cells (NK Cells) Are the "Born Killers" of Tumors. Tian Zhigang, an academician of the Chinese Academy of Engineering and a professor at the School of Basic Medicine, University of Science and Technology of China, once said: "Studies have shown that the content of NK cells in the human body is closely related to the occurrence of tumors. When the killing activity of NK cells is low, the incidence of tumors significantly increases."

For years, Tian Zhigang has led the R&D team in utilizing the NK cell target discovery platform to identify several groundbreaking original targets, providing new pathways for the treatment of cold tumors. In 2021, the R&D team founded Hefei TG ImmunoPharma Co., Ltd. (referred to as TGI).

Not long ago, two innovative immunotherapy drugs based on NK cell targets developed by TGI have successively initiated Phase I clinical trials at Peking University Cancer Hospital and Fudan University Shanghai Cancer Center, with the first patient enrolled and dosed in both trials.

Recently, Sun Haoyu, CEO of TGI, said in an interview with China Science Daily: "It only took us four years to move our research results from the laboratory to Phase I clinical trials. In the future, we plan to advance one to two innovative drugs into clinical trials each year."

Out of the Lab

NK cells are lymphocytes with cytotoxic functions, and they are an important part of the body's innate immune system. They also serve as the first line of defense against exogenous infections and malignant tumors, and are known as the body's "cancer-fighting guardian."

"They can quickly distinguish between 'self' and 'non-self' cells, and rapidly eliminate cells infected by pathogenic microorganisms and cancer cells." Sun Haoyu introduced that the inhibitory receptors on NK cells and their recognized ligands are a natural "treasure trove of drug targets."

Tian Zhigang has led his team in the NK cell and tumor immunology field for over 30 years. The team was among the first to discover that the tumor microenvironment can lead to NK cell exhaustion, and subsequently identified a group of immune checkpoint targets capable of reversing NK cell exhaustion, including novel immune checkpoints such as NKG2A and TIGIT, which have been widely validated by the scientific community. These immune checkpoints are also expressed on other immune cells, such as T cells, and blocking them can simultaneously restore the anti-tumor immune functions of both NK cells and T cells.

In Tian Zhigang's view, the true value of scientific research lies not only in discovering new knowledge but also in transforming research findings into treatment solutions that benefit patients.

As early as the 1990s, Tian Zhigang established China's specialized institution for immunotherapy — Shandong Tumor Biotherapy Research Center. He led his team to pioneer LAK cell therapy research in China and observed positive signals in clinical patients, witnessing the initial potential of immune cell therapy. The precursor cells of LAK cells include NK cells and T cells, and research on LAK cells laid the groundwork for subsequent exploration around NK cells.

Since joining the University of Science and Technology of China in 2001, Tian Zhigang has led his team to successfully translate multiple innovative achievements into applications, including Interleukin-12 (IL-12).

In recent years, the demand for innovative drug research and development has become increasingly urgent. Anhui Province has been actively promoting the development of the biopharmaceutical industry, with Hefei Economic Development Zone strategically positioning itself in the broader health sector and providing substantial support. Against this backdrop and opportunity, Zhigang Tian led his team out of the laboratory to establish TGI, officially embarking on a systematic and standardized path of technology transfer.

First-in-class Innovative Drug

"Developing first-in-class drugs not only lacks precedents but also faces high risks," Sun Haoyu told China Science Daily.

First, there is the unpredictability of species transition differences: the variations in drug responses across different species—from cells and mice in preclinical studies to monkeys in non-human primate research, and then to human trials—cannot be fully anticipated. Second, there is a lack of benchmark references: innovative drugs often target entirely new mechanisms, with no existing reference products, standard models, or technical tools available.

New targets need to be developed from scratch. To address these challenges, the founding team of TGI delved deeply into the mechanisms of target action, extensively utilized clinical samples for validation, and gradually established a research and development technology system for innovative targets by independently developing experimental models and platforms.

In December 2022, the clinical trial application for TGI's self-developed anti-PVRIG monoclonal antibody injection for the treatment of solid tumors received tacit approval from the U.S. Food and Drug Administration (FDA), and four months later, it was approved by China's National Medical Products Administration (NMPA).

Subsequently, TGI's self-developed bispecific antibody (TGI-6) and monoclonal antibody drug (TGI-5) successively received FDA's implied permission and NMPA's clinical trial application approval. Sun Haoyu said, "Receiving the clinical trial application approval is still very exciting, which means that we have moved from the early laboratory research stage to the clinical trial stage."

Sun Haoyu introduced that TGI-5 has completed the first patient enrollment and dosing at the Fudan University-affiliated Cancer Hospital in August this year. Currently, there are no products targeting the same point that have been approved for marketing worldwide. The drug exhibits high anti-tumor activity and good druggability, and is mainly used to treat indications such as colorectal cancer, hepatocellular carcinoma, HER2-negative breast cancer, melanoma, and non-small cell lung cancer.

TGI's another product, TGI-6, completed the enrollment of the first patient at Peking University Cancer Hospital in January 2024. It has therapeutic value for colorectal cancer and other solid tumors with positive targets, and it is the first bispecific antibody drug targeting the same target to enter the clinical stage in China.

Sun Haoyu revealed that the R&D team is very optimistic about the prospects of the TCE (T-cell engager) technology. Both T cells and NK cells are "anti-cancer weapons" in immunotherapy. Industry insiders believe that the TCE track holds great potential and has the opportunity to tackle difficult-to-treat solid tumors, but it can easily trigger cytokine storms, causing harm to the human body. How to widen the therapeutic window has become a challenge for the entire TCE field.

In response to this challenging field, TGI has developed the pH-selective TCE platform with independent intellectual property rights. By leveraging the acidic characteristics of the tumor microenvironment, the antibody drug is significantly activated only in the acidic tumor tissue, thereby substantially reducing peripheral toxicity. Current preclinical studies show that products developed based on this platform, such as TGI-10 and TGI-14, have achieved complete tumor eradication in various animal efficacy models, with lower peripheral toxicity compared to similar bispecific antibody drugs.

Cross-boundary Learning

"Doing scientific research in universities is completely different from developing products in companies. The only commonality is that talent and teamwork are both very important," Sun Haoyu told the reporter. Most of TGI's research and management teams have transitioned from academic research backgrounds, with limited initial experience in corporate governance, capital engagement, and business negotiations.

Taking Sun Haoyu as an example, she obtained her Ph.D. in Cell Biology from the University of Science and Technology of China in 2016 and conducted postdoctoral research at the Key Laboratory of Innate Immunity and Chronic Diseases, Chinese Academy of Sciences, in the same year. She observed: "Universities focus more on basic research and mechanisms of action, while companies not only require these theoretical foundations but also need technological breakthroughs and must consider the sustainable development of the company."

TGI's founding team has gradually introduced professional talents in management and operations through cross-disciplinary learning, strengthened external cooperation capabilities, and progressively established an operational management system suited for innovative drug development.

Nowadays, TGI is expanding from its initial NK cell innovative drugs to directions such as immune connectors (TCE, NKCE) and immune cytokines. It aims to both continue the team's technical advantages in original tumor immunology research and meet unaddressed clinical needs, balancing scientific ideals with market realities while systematically planning its product pipeline and long-term development path.

"We have accumulated resources and experience through financing and collaboration, gradually打通从研发到产业化的沟通链路, completing the transformation from a scientist team to an innovative enterprise operation team," said Sun Haoyu.