Chinese pharmaceutical companies have created another blockbuster drug | Jianzhi Research

Another representative transaction of innovative Chinese medicine has emerged, with Merck acquiring Tongrun Biotech's CD3xCD19 bispecific antibody CN201 project for a high price of USD 1.3 billion (USD 700 million upfront payment, USD 600 million milestone payment), setting a domestic record for bispecific antibody authorization.

In the field of biopharmaceuticals, TCE bispecific antibodies have become a market focus. T-cell engager (TCE) bispecific antibody technology, with its unique mechanism of action and significant clinical effects, is reshaping the landscape of cancer treatment and autoimmune disease therapy.

Merck's acquisition of Tongrun Biotech's CD3xCD19 bispecific antibody further demonstrates the enormous potential and market value of this technology.

1. Advantages of TCE Bispecific Antibodies: Specialized Tumor Killing Power and Memory Effect

TCE bispecific antibodies are innovative biopharmaceutical antibodies that can simultaneously bind to two different antigens.

In a typical TCE bispecific antibody, one end specifically binds to the CD3 molecule on the surface of T cells, while the other end binds to a specific antigen on the surface of tumor cells or cells related to autoimmune diseases (such as CD19).

This unique design allows TCE bispecific antibodies to bring T cells closer to target cells in space, thereby activating T cells and guiding them to selectively kill target cells.

Compared to traditional monoclonal antibodies, TCE bispecific antibodies have a more direct and powerful cell killing mechanism. Traditional monoclonal antibodies mainly function through mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cell phagocytosis (ADCP), which mainly rely on NK cells and macrophages, rather than specialized anti-tumor effector cells.

TCE bispecific antibodies directly activate and guide T cells to kill target cells, a mechanism that is more similar to the highly anticipated CAR-T cell therapy. Therefore, in terms of indications, TCE is also similar to CAR-T, with autoimmune diseases becoming the next trend besides tumors.

A significant advantage of TCE bispecific antibodies is their strong specialized cell killing ability. By directly activating T cells, TCE bispecific antibodies can induce a stronger and more durable immune response.

Furthermore, the memory characteristics of T cells may allow patients treated with TCE bispecific antibodies to obtain long-term immune surveillance, which often manifests as a significant extension of overall survival (OS) in clinical data.

For example, Amgen's AMG757 has shown outstanding results in the treatment of small cell lung cancer, with a progression-free survival (PFS) of 3.7 months and an overall survival (OS) of 13.2 months, nearly 3 times that of PFS, fully demonstrating the importance of T cell memory effect.

2. After the hematologic market, the market is more looking forward to the self-immunity field

TCE bispecific antibodies have shown good clinical efficacy in the field of hematologic tumors. There are a total of 7 TCE bispecific antibody products approved and marketed in hematologic tumors, covering targets such as BCMA, GPRC5D, CD20, and CD19, approved for multiple indications such as multiple myeloma, diffuse large B-cell lymphoma, etc. Among them, Johnson & Johnson expects sales of nearly $5 billion for its two products, Talquetamab (GPRC5D/CD3) and Teclistamab (BCMA/CD3).

However, the market has higher expectations for TCE in the self-immunity field.

Taking Amgen's Blinatumomab as an example, its sales in the first half of the year were $264 million, a year-on-year increase of 28%; but the company emphasized its leading progress in clinical trials in the self-immunity field during the conference call.

This is also why Merck was able to offer an initial payment of $700 million to acquire Tongren Biotech's CN201 (CD19/CD3 bispecific antibody) project, as it values more its potential in the field of autoimmune diseases. In addition to Tongren domestically, in August 2024, Jiahe Biotech's GB261 (CD20/CD3 bispecific antibody) also successfully went overseas.

The application of TCE bispecific antibodies in the treatment of autoimmune diseases is an exciting new field. Its mechanism of action is based on the following theoretical basis:

• B cell clearance: Similar to CD3/CD19 or CD3/CD20 bispecific antibodies used in hematologic tumor treatment, TCE bispecific antibodies can effectively clear abnormal B cells.
• Immune system reset: After clearing abnormal B cells, the bone marrow can regenerate healthy B cells, potentially "resetting" the immune system.
• Persistence effect: Due to the memory characteristics of T cells, TCE bispecific antibody treatment may provide long-term immune surveillance to prevent disease recurrence.

With the potential long-term efficacy of CAR-T therapy in SLE, overseas MNCs, such as Roche's CD20/CD3 bispecific antibody and Amgen's BCMA/CD3 bispecific antibody, are conducting clinical trials of TCE bispecific antibodies in self-immunity indications.

However, TCE has its own advantages over CAR-T in the self-immunity field:

• Safety: The rapid proliferation of CAR-T cells may lead to severe CRS, while TCE bispecific antibodies can better control this risk by adjusting the dosage

• Controllability: TCE bispecific antibodies can be dose-escalated, while CAR-T therapy typically requires a one-time infusion, resulting in lower flexibility in operation.
• Accessibility: CAR-T therapy involves complex individualized preparation, while TCE bispecific antibodies, as "off-the-shelf" drugs, are easier to promote and use.

In June 2024, Amgen's Blinatumomab (CD19/CD3) was first published in the ITT data of systemic sclerosis (SSc) in the "European Journal Of Cancer". The results showed that Blinatumomab can achieve deep B cell depletion, leading to improvements in skin scores (mRSS) and peripheral perfusion, with good safety.

With more positive clinical news about TCE bispecific antibodies, it will further open up a broad space for self-immune disease.

3. Breakthrough in Solid Tumor

In addition to hematologic malignancies, TCE bispecific antibody technology has also made remarkable progress in the field of solid tumor treatment.

Amgen's TCE bispecific antibody Tarlatamab targeting CD3-DLL3 has shown excellent clinical efficacy in the treatment of small cell lung cancer and has been approved by the FDA. In Phase II clinical trials, Tarlatamab achieved objective response rates (ORR) of 40% and 32% in the 10mg and 100mg dose groups, with median progression-free survival (mPFS) of 4.9 months and 3.9 months, respectively.

This breakthrough has opened up a new path for the application of TCE bispecific antibodies in the field of solid tumors.

A major challenge in solid tumor treatment is the complex tumor microenvironment, which often inhibits the function and infiltration of immune cells. TCE bispecific antibodies demonstrate unique advantages in overcoming this barrier:

• Effective recognition of low-expressed targets: Unlike therapies such as ADC that require high target expression, TCE bispecific antibodies have lower requirements for target expression. For example, although DLL3 is not highly expressed in small cell lung cancer, it is highly specific, and TCE bispecific antibodies can still effectively recognize and function.
• Recruitment and activation of T cells: TCE bispecific antibodies can effectively recruit and activate more T cells through cascading activation pathways, enhancing the infiltration capability against solid tumors.
• Combination therapy strategies: Researchers are exploring the combination of TCE bispecific antibodies with other therapies (such as chemotherapy, ADC) to further improve the tumor microenvironment and enhance treatment efficacy.

The combination of TCE bispecific antibodies and ADC shows great potential, breaking through the immune-suppressive tumor microenvironment.

For example, Daiichi Sankyo and Merck are collaborating to develop a combination therapy of CD3 BCMA and BCMA ADC. This combination may become a prototype of the next generation of immunotherapies, providing patients with more effective treatment options

4. Domestic Company Progress

In terms of domestic TCE bispecific indications, blood tumors are the main focus. Listed companies involved in the layout of TCE bispecifics include Zejing Pharmaceutical, Zhixiang Jintai, Kannoah, Bailing Tianheng, Boan Biotech, Junshi Biosciences, Xinda Biotech, etc. Among them, Zejing Pharmaceutical and Kannoah focus on solid tumors, while Bailing Tianheng specializes in antibody formats for four indications.

1. BeiGene:

   • Collaborating with Amgen on Tarlatamab, holding market rights in China
   • Independently developing BCMA x CD3 bispecifics

2. Kannoah:

   • Developing multiple bispecific products based on its proprietary nTCE platform
   • Product line covers blood tumors and solid tumors

3. Zejing Pharmaceutical:

   • Developing the tri-specific antibody ZG006 (DLL3 x CD3) targeting small cell lung cancer
   • Patents covering DLL3, BCMA, PSMA, and other targets

4. Bailing Tianheng:

   • Patents covering DLL3, BCMA, PSMA, and other targets
   • Pioneering the GNC tetra-specific antibody platform globally, with tumor-targeting CD19, EGFRvIII, ROR1, and multiple projects in progress

Conclusion

TCE bispecific antibody technology represents a major breakthrough in the fields of tumor immunotherapy and autoimmune disease treatment.

It has shown outstanding efficacy not only in the treatment of blood tumors but also holds great potential in solid tumors and autoimmune disease treatment. With continuous optimization of the technology and expansion of clinical applications, TCE bispecifics are expected to become another significant opportunity in the biopharmaceutical field following monoclonal antibodies and CAR-T therapies.

Merck's acquisition of Tongren Biotech's CD3xCD19 bispecific project not only highlights the value of this technology but also once again demonstrates the research and development capabilities of innovative pharmaceutical companies in China