ORR 100%! Domestic Trispecific Antibody Clinical Data Surge, with TCE, NKCE, and Immune Checkpoint-Targeting Trispecifics Driving Differentiated Competition
Innovent
High-end Biologics Developer
Qilu Pharmaceutical
Specialty Formulations and Active Pharmaceutical Ingredients (API) Developer
Zelgen
Innovative Drug Research and Development, Manufacturer
Johnson & Johnson
Medical Device R&D and Manufacturer
November 21, 2025
eMedClub News
Hotspots favored by MNCs,
The "Three Antibodies" Track Continues to Heat Up
From the perspective of the track background, the bispecific antibody field has entered the harvest period, but it is gradually encountering obstacles such as "on-target off-tumor" toxicity in solid tumors and antigen loss drug resistance in hematological tumors. However, trispecific antibodies, with their "multi-target synergy" characteristics, can cover more mechanisms through combined targets while reducing the risk of drug resistance caused by reliance on a single target, making them an important direction for the next generation of antibody technology.
According to public data, currently globallyMore Than Three Antibody Drugs Under ResearchHundreds of Products, of which about one-third have entered the clinical stage.China is one of the most active regions in the development of "three antis"., not only has a large number of pipeline layouts, but also has formed differentiation in terms of target differentiation and structural innovation.
The popularity of triple-target drugs can also be seen in recent transaction cases.
November 2025,Boehringer Ingelheim（BI）Entered into a $570 million licensing agreement with CDR-Life, granting the latter global development and commercialization rights for the novel CD19/BCMA/CD3 TCE drug, CDR111. The drug is intended for the treatment of autoimmune diseases.
In July of the same year,AbbVieAbbVie Acquires IGI Therapeutics SA's CD3/CD38/BCMA Trispecific Antibody ISB 2001 for $700 Million Upfront to Treat Multiple Myeloma. This marks another move by AbbVie in the hematological oncology field this year.
Merck & Co.Similarly, it is an active player in the tri-specific antibody field. In 2024, Merck acquired Harpoon Therapeutics, a TCE development company, for $680 million, obtaining the DLL3/CD3/albumin tri-specific antibody HPN328.（MK-6070）A series of TCEs led by. Subsequently, Merck once again with$1.3 billion upfront and up to $1.7 billionMilestone Acquisition of EyeBio and Its Core Product - Tetravalent Trispecific Antibody Restoret（EYE103）, to develop drugs for retinal diseases.
China's Biotech Also Active in Tri-specific Antibody Deals. January 2025,Simcere PharmaceuticalSIM0500, a triple-antibody therapy from Innovent Bio, successfully secures over $1 billion deal authorization from AbbVie.Vivoly BiologicsCompanies such as Innovent Bio, Qilu Pharmaceutical, Zelgen, Johnson & Johnson, and others are also actively expanding collaborations on a global scale.
Three Major Technical Pathways Proceeding in Parallel
Compared with bispecific antibodies, trispecific antibodies add a specific antigen binding site, enabling them to achieve more complex therapeutic mechanisms. Currently, trispecific antibodies can be classified according to their mechanisms of action.T Cell Engager（TCE）, NK Cell Engagers and Targeted Immune CheckpointsAnd many other types.
Each technical pathway has its own characteristics, and the layout of indications also shows differentiation.
T Cell Engager (TCE)
T Cell Engagers: One of the Mainstream Technical Directions in the Tri-specific Antibody Field
The targeting combination modes of TCE tri-specific antibodies are flexible and diverse, including not only CD3/TAA/TAA, but also various types such as T cell Marker/TAA/TAA and T cell Marker/T cell Marker/TAA.
"CD3/TAA/TAA" Architecture Remains the Mainstream StrategyCurrently, more than half of the TCE trispecific antibody clinical pipelines adopt this model, but the selection of TAAs is becoming increasingly differentiated, including BCMA, GPRC5D, CD20, CD79b, CD19, HER2, DLL3, MUC17, MSLN, CDH3, CLDN6, WT1, etc.
Based on this architecture,The Introduction of Immune Co-stimulatory Molecules to Enhance T-cell Activity Becomes an Important TrendThis design theoretically enhances the sustained killing ability of T cells while reducing the risk of cytokine release syndrome caused by overactivation, by simultaneously activating the first and second signals of T cells.
CD28 and 4-1BB are the two most commonly used co-stimulatory molecules, each with multiple projects under research. Representative pipelines for the former include Huihe Bio's CD3/CD19/CD28 trispecific antibody CC312 and 3SBio's CD3/CD28/MUC17 trispecific antibody SSS59; representative pipelines for the latter include Roche's CD3/DLL3/4-1BB trispecific antibody RO7616789, Chugai's CD3/4-1BB/CLDN6 trispecific antibody SAIL 66, and Leplibody's CD3/4-1BB/WT1 trispecific antibody CTM012, among others.
In addition,Design of Functional Module IntegrationIt is also an optimization strategy for TCE tri-specific antibodies. For instance, MK-6070, acquired by Merck for $680 million through the acquisition of Harpoon, extends the drug's circulation time in the body by incorporating an anti-albumin domain, leveraging albumin’s long half-life to further enhance drug stability and pharmacokinetic properties.
In terms of indications,Multiple MyelomaHematological tumors, represented by [specific type], are the main battleground for TCE trispecific antibodies, attracting numerous domestic and international companies such as Keyuan Bochuang/Tian Guangshi, Innovent Bio, Simcere Pharma, Qilu Pharmaceutical, Johnson & Johnson, and AbbVie to establish their presence. Some of these companies have already advanced to Phase 1/2 clinical trials.
This clustering phenomenon may be related to the targeting advantages and rich data accumulation of mature hematological tumor targets such as BCMA, GPRC5D, and CD19.
Notably, TCE tri-specific antibodies have also shown promising results recently in the fields of solid tumors and autoimmune diseases.Small Cell Lung Cancer（SCLC）It is the preferred indication for TCE bispecific antibodies in the solid tumor field, and the same applies to TCE trispecific antibodies. Companies such as Merck, Zelgen, and Roche have already established relevant pipelines, with the core focus on targeting the DLL3 pathway.
The pipeline layout in the field of autoimmune diseases is becoming a hot area for pharmaceutical companies and multinational corporations (MNCs) to invest in. QLS4131 from Qilu Pharmaceutical, CMG1A46 from GSK/Entremed Biotech, CC312 from Huihe Bio, and PIT565 from Novartis all include systemic lupus erythematosus or a broader range of autoimmune diseases as part of their indications.
NK Cell Engager
NK Cell Engagers: Another Key Technological Pathway by Recruiting and Activating Natural Killers（NK）Cells, rather than T cells, are used to kill tumor cells. These trispecific antibodies typically target activating receptors on the surface of NK cells.(such as CD16, NKp46, etc.)And tumor antigens.
As early as 2016, Sanofi signed a cooperation agreement with Innate Pharma to jointly develop two NK cell engagers: the NKp46/CD16/CD123 trispecific antibody SAR443579 and the NKp46/CD16/BCMA trispecific antibody SAR445514.
On April 23, 2025, Innate announced that the company has regained global rights to SAR443579. Reportedly, the Phase 1/2 clinical study of SAR443579 previously led by Sanofi is still ongoing, and the disclosed dose-escalation efficacy and safety data also indicate some clinical benefits and durable responses.
Another tri-specific antibody, SAR445514, was originally intended for the treatment of multiple myeloma. However, considering the company’s current strategic direction, Sanofi has decided to terminate its Phase 1/2 clinical trial early and instead focus on advancing the drug’s development in the field of autoimmune diseases.
October 8,Cell Subsidiary JournalCell Reports MedicinePublished a research paper titled "A nanobody-based tri-specific NK cell engager targeting CD5 triggers antitumor immunity." The research team developed aTrispecific NK Cell Engagers Based on NanobodiesBy targeting CD5, it exhibits a stronger anti-tumor effect on CD5+ malignant tumor cells. Compared with CD5-CAR-T cells, this trispecific NK cell engager can avoid off-target toxicity effects on normal T cells.
The research team further introduced IL-15Rα/IL-15, and the modified trispecific NK cell engager exhibited stronger antitumor effects on CD5+ malignant tumor cells, producing more cytokines and chemokines.
Immune Checkpoint Targeting Tri-Specific Antibody
Immune checkpoints (such as PD-1/PD-L1, CTLA-4, etc.) are key mechanisms for tumor cells to evade immune attacks. Such tri-specific antibodiesBy combining immune checkpoint molecules, blocking their interaction with ligands, relieving the inhibition on T cells, and restoring the anti-tumor activity of T cells.
November 4, 2025CStone PharmaceuticalsSuzhou Zelgen Biopharmaceuticals Co., Ltd. announced that the Phase 2 clinical trial application for its self-developed trispecific antibody CS2009 combination therapy for advanced solid tumors has been approved by China's NMPA. The drug targets three clinically validated targets—PD-1, VEGFA, and CTLA-4—achieving multi-dimensional anti-tumor effects through synergistic action.
Specifically, blocking PD-1 can reverse T-cell exhaustion, blocking CTLA-4 can promote T-cell activation and proliferation, and blocking VEGFA can inhibit tumor angiogenesis, thereby improving the tumor microenvironment.（TME）In the TME, the dual blockade of PD-1 and CTLA-4 is significantly enhanced through crosslinking with VEGFA. Meanwhile, CS2009 preferentially binds to tumor-infiltrating T cells that are double-positive for PD-1 and CTLA-4, minimizing interference with the CTLA-4 regulatory pathway in peripheral T cells.
Previously, at the 2025 ESMO Annual Meeting, CStone Pharmaceuticals disclosed preliminary data from the Phase 1 clinical study of CS2009 for the first time. It is reported that,This is also the first known publication of clinical data on a PD-1/VEGF/CTLA-4 tri-specific antibody.。
As of the poster data cutoff date, anti-tumor activity of CS2009 was observed in all dose groups, showing a dose-dependent upward trend. The overall ORR was 12.2%, and the DCR was 71.4%. Efficacy data are still maturing; during the follow-up period after the poster data cutoff date, the overall ORR increased to 14.3%. At the provisional recommended phase 2 dose.（RP2D，30 mg/kg）Higher ORR was observed at higher doses.（25.0%）。
At the same time, efficacy signals were observed across multiple tumor types despite the relatively short follow-up period. More NSCLC patients achieved stable disease.（SD）Improved to Partial Remission（PR），As of now, the ORR in this population has increased to 17.6%. In driver genes（AGA）In the negative subgroup, the objective response rate reached 25%.
In addition to CS2009,Hongcheng PharmaceuticalA tri-specific antibody targeting PD-1/CTLA-4/VEGF, HC010, is currently in the clinical stage, and a Phase 2 clinical study for first-line treatment of PD-L1 positive advanced non-small cell lung cancer was initiated on November 6.
Opportunities and Challenges Coexist
Despite the great potential exhibited by trispecific antibodies, their development still faces many challenges.
SafetyIs the primary consideration, especially for the management of CRS and immune-related adverse reactions; the structural complexity of trispecific antibodies also presents manufacturing challenges; target selection is not a simple叠加, but requires a delicate balance of affinity and specificity for each target.
In addition, the optimal dosing strategy and dose optimization for trispecific antibody drugs need to be further explored in larger-scale clinical trials.
Despite this, the development prospects of trispecific antibody drugs remain broad. With more clinical data being read out, trispecific antibodies are expected to achieve breakthroughs in multiple therapeutic fields.
Ophthalmology FieldOne of the fields that may become the first breakthrough in triple resistance. Restoret, which Merck obtained from EyeBio.（EYE103）It has now entered the pivotal Phase 2/3 clinical trial, with the indication being diabetic macular edema. In the Phase 1b/2a clinical trial, 26 patients with DME were treated.Best-corrected visual acuity improved by 11.2 letters, and retinal thickness decreased by 80%.。
In the future, with continuous technological iteration and innovation, further expansion of indications, and the application of combination therapies, trispecific antibody drugs will validate their efficacy in more and larger-scale clinical trials.
Editor-in-Chief | Xuan Xiao
Proofread by | Xuan Xiao
References:
1.Official websites, official WeChat accounts, and public materials of various companies
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