Pioneering next-gen T-cell engagers: CentryMed seeks HK listing

On November 12, the HKEX disclosed that Zhejiang Shimai Pharmaceutical Co., Ltd. - B ("CentryMed") has submitted an application to list on the HKEX Main Board, with Huatai International acting as the exclusive sponsor.

Founded in 2017, CentryMed is a pioneer and global leader in next-generation T-cell engager (TCE) therapies. The company has developed a pioneering masked TCE designed for selective activation within tumors, specifically addressing the challenges of treating solid tumors. Following three rounds of equity financing, CentryMed's post-money valuation reached RMB 2.23 billion after its Series C round in January 2022.

How is this clinical physician-founded biotech positioning itself as "China's pioneering next-generation solid tumor TCE stock" to the capital markets?

As one of the most prominent bispecific mechanisms of action, the design principle of T-cell Engagers (TCEs) involves simultaneously binding to Tumor-Associated Antigens (TAA) on tumor cells and the CD3 receptor complex on T cells. This directs the T cells to the tumor site and activates them to induce targeted cytotoxicity.

Mechanistically, the advantages of TCEs are twofold. On one hand, they precisely and sustainably activate all available T cells, utilizing various TAAs as targeting antigens for direction. On the other hand, TCEs minimize excessive immune activation, providing a manageable solution for Cytokine Release Syndrome (CRS) and offering significant safety benefits.

Concurrently, TCE designs have evolved from the early 1+1 format (one TAA binding domain + one T cell binding domain) to increasingly include masked, multifunctional, and logic-gated forms. Their indications are also progressively expanding from hematologic malignancies to solid tumors.

Solid tumors represent a major clinical gap, accounting for 90% of total cancer cases. A notable trend indicates that the number of TCE drugs under investigation for solid tumors is growing faster than that for hematologic malignancies. However, to date, only two TCE drugs for solid tumors have gained global approval: Amgen's Tarlatamab and Immunocore's Tebentafusp. The fundamental challenge lies in the biological characteristics of solid tumors (e.g., tumor microenvironment, physical barriers), which impose higher demands on TCEs—specifically, the challenge of finding the balance between the therapeutic window, toxicity, and potency (efficacy).

CentryMed identified this gap early, focusing on applying TCE technology, particularly next-generation masked TCEs, to address the key challenges in solid tumor treatment: Cytokine Release Syndrome (CRS), limited tissue penetration, the lack of reliable biomarkers, and acquired resistance. In 2018, the company established three of the world's largest fully human IgM phage display antibody libraries, along with the H-BiTE platform. In 2021, it built a fourth large-capacity fully human IgM phage display antibody library, laying a solid foundation for antibody screening.

Also in 2021, CentryMed formulated the industry's first CAESAR Guide, which serves as the development standard for its next-generation TCE therapies:

·Controllable Adverse Effects: Enhancing CRS management and selective activation.

·Activation Efficiency: Efficient, one-step cleavage of the masking peptide for potent T-cell activation.

·Effective Infiltration: Improved tissue penetration and activation within the tumor microenvironment.

·Scalability: A next-generation TCE production system.

·Anti-Resistance Capability: Sustained and stable tumor killing kinetics.

·Reliable Biomarkers: Supporting patient identification and treatment response monitoring.

These technological breakthroughs have led to a paradigm shift in dosing. Simply put, CentryMed's proprietary technology has increased the typical TCE dose from around 100 micrograms per patient to approximately 10 milligrams—a hundredfold improvement in the safety-efficacy window. Under the premise of controllable CRS, the new-generation TCEs can achieve sufficiently high effective dose levels, activate various T-cell subsets, and deliver "potent killing" effects, offering a highly effective solution for late-line and solid tumor treatments.

For next-generation TCEs to potentially advance into frontline therapy in oncology, they must not only widen the therapeutic window, enable higher effective dosing, and achieve potent killing with the first dose, but also deliver more durable clinical responses.

CentryMed remains patient-centric and driven by clinical needs, dedicated to developing first-in-class, functionally differentiated antibody therapeutics for malignant tumors. Translating this into practice, the company's current innovation logic revolves around continuously iterating its T-cell engager (TCE) platforms in response to evolving real-world requirements.

The company has established four core technology platforms: a multi-channel antibody discovery platform, an H-form bispecific TCE platform (H-BiTE), a protease-activated bispecific TCE platform (Pro-BiTE), and a multifunctional/logic-gated TCE platform. To date, four candidate drugs have entered the clinical development stage, comprehensively covering all four iterations of TCE technology.

Product DNV3 is a potential best-in-class T-cell modulator (TCM) targeting the immune checkpoint receptor Lymphocyte Activation Gene-3 (LAG-3). Among anti-LAG-3 antibody candidates for melanoma treatment, it ranks second globally and in China by clinical development stage, and is currently undergoing a Phase II clinical trial for melanoma in combination with an anti-PD-1 antibody.

Data show DNV3 delivers doubled efficacy for LAG-3-targeting drugs:

Among 18 patients with mucosal melanoma previously treated with PD-(L)1 inhibitors, the DNV3 combination therapy achieved an objective response rate (ORR) of 44.4%, approximately three times higher than existing comparable therapies.

Among 12 patients with cutaneous melanoma, the ORR was 66.7%, over five times higher than the ORR of existing comparable therapies.

In patients with hepatic metastatic melanoma for whom no effective treatment is currently available, the combination therapy achieved an ORR of 38.5% and a median progression-free survival (mPFS) of 7.4 months.

Regarding immunotherapies targeting the same mechanism, only one anti-LAG-3 monoclonal antibody—Bristol Myers Squibb's (BMS) relatlimab—has been approved globally. It is used in combination with nivolumab (the anti-LAG-3/PD-1 dual-immunotherapy fixed-dose combination Opdualag) as a first-line treatment for advanced melanoma. Approved for this single indication, Opdualag generated USD 928 million in revenue for BMS in 2024, representing a 48% growth rate. Currently, Opdualag has initiated a Phase III clinical trial for first-line combination therapy in non-squamous non-small cell lung cancer, compared with Pembrolizumab.

Derived from the plug-and-play, bispecific T-cell engager (TCE) platform H-BiTE, the second-generation TCE platform emphasizes "small molecule size and low risk." It offers advantages including low molecular weight (enabling solid tumor penetration), reduced risk of cytokine release syndrome (CRS) (supporting intravenous administration), and binding activity based on gene expression (enabling potential adaptation across multiple tumor types).

A representative drug, SMET12, is the first EGFR×CD3 TCE globally to enter Phase II clinical trials. As a potential first-in-class, fully humanized EGFR×CD3 TCE for intravenous administration, it ranks first in clinical progress among all global and Chinese EGFR×CD3 TCE candidates. By focusing on the classic tumor target EGFR, the EGFR×CD3 TCE leverages a dual-targeting mechanism to produce synergistic tumor-killing effects, showing promise in addressing core drug resistance issues.

Currently, no EGFR×CD3 TCE products have been approved for marketing worldwide. SMET12 has now initiated a Phase IIa clinical trial targeting EGFR-positive advanced solid tumors, including esophageal cancer.

Data from an Investigator-Initiated Trial (IIT) showed that among 12 NSCLC patients with EGFR mutations resistant to TKI therapy, SMET12 combined with toripalimab and chemotherapy achieved a disease control rate (DCR) of 100%, an objective response rate (ORR) of 41.7%, and a median progression-free survival (mPFS) of 7.2 months. In the Phase I clinical trial, no dose-limiting toxicities were observed for SMET12 within the 10–120 µg dose range.

Another candidate, CMD011, is a potential best-in-class GPC3×CD3 TCE. It has commenced a Phase I clinical trial in China for advanced hepatocellular carcinoma (HCC) and received FDA Investigational New Drug (IND) approval in February 2025. Among GPC3×CD3 TCE candidates, CMD011 ranks in the top two globally by clinical development stage.

The core of the protease-activated bispecific T-cell engager (TCE) platform (Pro-BiTE) is a "masking peptide switch"—the drug remains dormant in normal tissues and systemic circulation but is activated by specific proteases upon entering the tumor. This mechanism reduces off-target toxicity while generating sufficiently high effective drug levels within the tumor microenvironment (TME), enabling potent tumor-killing effects.

A product from this platform, CMDE005, is a potential first-in-class masked EGFR×CD3 TCE. It is currently undergoing a Phase I clinical trial in China for the treatment of various EGFR-positive advanced solid tumors and received FDA Investigational New Drug (IND) approval in April 2025. Among EGFR×CD3 TCE candidates, CMDE005 ranks among the top two globally and is the first and only TCE in China that has entered the clinical stage utilizing masking peptide technology, demonstrating potential to establish TCEs as a cornerstone therapy in oncology.

Interim results from the ongoing Phase I clinical trial show that CMDE005 elicits dose-dependent immune responses and efficacy, with favorable human tolerability and manageable side effects. At doses up to 3 mg, no Grade 3 or higher adverse events (AEs) or serious adverse events were observed. Notably, preliminary signs of efficacy have been observed in patients with non-small cell lung cancer (NSCLC).

The multifunctional/logic-gated TCE platform launches coordinated targeted attacks against tumors by simultaneously blocking immune checkpoints and activating T cells. This enhances T cell activation, prevents T cell exhaustion, and improves tumor-killing capacity. The multifunctional TCE employs an OR-gate dual-target design or multi-target strategy, simultaneously targeting one or two TAAs along with the T cell receptor. This effectively addresses challenges such as antigen loss, mutation, and tumor heterogeneity. By inhibiting T cell exhaustion, it helps prevent tumor recurrence and ensures a more potent and durable immune response.

Under this platform, CentryMed has advanced two preclinical candidate drugs: CMDE101 (targeting FOLR1×PD-L1×CD3) and CMDE102 (targeting PSMA×PD-L1×CD3). Both are trispecific masked TCEs.

Dr. Xiao Zuoxiang, founder of CentryMed, graduated from Zhejiang University and is a Senior Engineer in Biopharmaceuticals. He previously held positions at world-leading medical research institutions, including the Johns Hopkins Bloomberg School of Public Health, the Johns Hopkins University School of Medicine, and the National Cancer Institute (NCI) in the United States. His accomplishments include the first-ever establishment of a mouse model for non-small cell squamous cell carcinoma and the discovery that zinc chelators can effectively inhibit HIV viral replication. With over 30 years of experience in oncology clinical practice, pathogenesis research, and innovative antibody drug development, he also has more than a decade of experience as a clinical oncologist.

This background has established the core DNA of CentryMed—"anchored in clinical value"—which consistently guides its work under two key principles:

·While effectively treating diseases, do not increase patient suffering or toxic side effects.

·Ensure treatments are affordable and beneficial for the vast majority of patients.

This logic is directly reflected in the company's TCE product development, exemplified by its repeated emphasis on reducing CRS risk and managing adverse reactions. At a deeper level, this high focus on safety implies cost control and improved patient accessibility:

TCEs inherently offer cost advantages, as the dosage required is only a fraction—dozens to hundreds of times lower—than that of traditional drugs, while production yields remain comparable, fundamentally reducing treatment costs.

Early TCEs often relied on continuous infusion pumps and inpatient monitoring, increasing treatment burden and limiting patient acceptance. In contrast, SMET12—the world's first intravenously administrable EGFR×CD3 bispecific antibody—used in combination with PD-1 inhibitors, not only enhances efficacy but also improves acceptance among physicians and patients, facilitating broader clinical adoption.

The "safe + economical" profile points to broader addressable markets and greater commercial potential.

Looking further ahead, next-generation TCEs hold extensive possibilities yet to be explored, advancing toward precision, multifunctionality, and intelligent design, with significant untapped potential in targeting accuracy and combined killing mechanisms.

Positioning for the future, CentryMed is also exploring AI-assisted TCE design. As mentioned in its prospectus, TCEs are particularly suitable for AI-driven approaches because their development success depends on coordinating the complex multi-factor interactions among the drug, T cells, and cancer cells. In the future, AI applications will be deeply embedded across the entire R&D process—spanning from molecular design and functional prediction to clinical risk assessment.

As a pre-revenue biotech company, CentryMed has demonstrated positive signals of narrowing losses and stabilizing cash flow. The company's net loss decreased from RMB 74.943 million in 2023 to RMB 59.899 million in 2024 and further narrowed to RMB 25.42 million in the first half of 2025, primarily due to optimized R&D expense management.

The balance of cash and cash equivalents has shown a positive trend alongside the company's development. It stood at RMB 24.831 million in 2023, was maintained at RMB 23.907 million in 2024, and increased to RMB 85.739 million as of June 30, 2025.

In terms of funding, CentryMed has completed three rounds of financing, attracting continued support from leading industry players such as Betta Pharmaceuticals (through its subsidiary Betta Bio), Tigermed, and MabPlex International. For a biotech company, this represents valuable industry chain resources and ecosystem support.

Against the backdrop of TCE therapeutics becoming a focus in global innovative drug business development and the urgent need for solid tumor treatments, CentryMed—equipped with four generations of technology platforms and four core clinical-stage drug candidates—is now advancing toward a Hong Kong listing, positioning itself as "the first Chinese next-generation solid tumor TCE stock." This move may potentially carve out new territory for China's innovative drug sector.