Trispecific Antibodies: The Next Frontier in Immunotherapy Gains Momentum with Big Pharma Investments
核心洞察
More than 100 trispecific antibody candidates are in development worldwide as of May 2026, though none have yet received regulatory approval.
Merck (搜索)'s Restoret (MK-3000) is the first trispecific antibody to enter a Phase 2b/3 trial, being evaluated for diabetic macular oedema (搜索).
Johnson & Johnson's JNJ-79635322 demonstrated an 86.1% overall response rate in early Phase 1 data, rising to 100% in patients without prior BCMA (搜索)- or GPRC5D (搜索)-directed therapies.
Trispecific antibodies are rapidly emerging as the next frontier in antibody therapeutics, building on the clinical success of bispecific antibodies and attracting billions of dollars in licensing and acquisition deals from major pharmaceutical companies. As of May 2026, more than 100 trispecific antibody candidates were in development worldwide, according to ScienceDirect, though none have yet received regulatory approval.
The field has gained particular momentum as researchers seek to overcome the limitations of current immunotherapies, especially in solid tumours. "Traditional immunotherapies, including checkpoint inhibitors, rely on patients' pre-existing tumour-reactive T cells and often struggle to activate immune responses in immunosuppressive 'cold' tumours, resulting in limited efficacy and widespread treatment resistance in solid tumours," said Dr Lei Fang, Co-founder, Chairman and CEO of Excalipoint Therapeutics (搜索).
Clinical Pipeline Advancing Rapidly
Among the most advanced programmes, Merck (搜索)'s Restoret (MK-3000, formerly EYE103), being developed in partnership with EyeBio, has become the first trispecific antibody to enter a Phase 2b/3 clinical trial. The candidate is being evaluated for diabetic macular oedema (搜索) (DME), a condition that poses a significant threat to vision and quality of life.
Innovent Biologics (搜索) has dosed the first patient in TriadicMM-1, a pivotal Phase 3 trial evaluating IBI3003, a GPRC5D (搜索)/BCMA (搜索)/CD3 (搜索) trispecific antibody, in patients with relapsed or refractory multiple myeloma (搜索). This programme is only the second trispecific antibody globally to reach pivotal Phase 3 development in this indication and the first with independently owned intellectual property in China.
Big Pharma Commits Billions
The rapid progress has attracted considerable investment. In March 2026, Sanofi licensed Kali Therapeutics' KT501 (搜索), a CD3 (搜索)/CD19 (搜索)/BCMA (搜索) trispecific T-cell engager for B-cell-mediated autoimmune diseases, in a deal worth $180 million upfront. The candidate is currently being evaluated in a first-in-human trial for rheumatoid arthritis (搜索) after demonstrating potent B-cell depletion and reduced cytokine production in preclinical studies.
AbbVie (搜索) paid $700 million upfront to Ichnos Glenmark Innovation (IGI) for ISB 2001, a CD38 (搜索)×BCMA (搜索)×CD3 (搜索) trispecific antibody being developed for multiple myeloma (搜索) and autoimmune diseases.
Johnson & Johnson and Pfizer are expanding trispecific development beyond oncology. Early Phase 1 data for Johnson & Johnson's JNJ-79635322 showed an overall response rate of 86.1%, increasing to 100% in patients who had not previously received BCMA (搜索)- or GPRC5D (搜索)-directed therapies, while demonstrating an encouraging safety profile. Pfizer reported positive Phase 2 results for its trispecific antibody candidate in patients with moderate-to-severe atopic dermatitis (搜索) and plans to advance into a pivotal Phase 3 trial later this year.
China as an Innovation Hub
China is rapidly establishing itself as a global centre for trispecific antibody innovation. Excalipoint Therapeutics (搜索) launched in March 2026 with $68.7 million in funding to develop next-generation T-cell engager therapies. CStone Pharmaceuticals is developing CS2009, a PD-1 (搜索)/VEGF (搜索)/CTLA-4 (搜索) trispecific antibody, while Huahui Health signed a $1.9 billion licensing and collaboration agreement with BeOne Medicines for HH160 (搜索), a novel trispecific antibody for oncology immunotherapy.
"China is emerging as a global hub for engineered immunotherapy development, supported by mature clinical trial infrastructure, robust manufacturing capacity and unique patient access advantages," said Dr Fang.
Platform Technologies and Future Directions
Excalipoint has built proprietary platforms—EXCOPIA (co-stimulatory), EXiShield (immune shield) and EXPROMA (probody)—designed to remodel the immunosuppressive tumour microenvironment and convert immune 'cold' tumours into 'hot' tumours. The company's lead asset, EXP011 (搜索) (DLL3 (搜索)/CD3 (搜索)/4-1BB (搜索)), has gained industry recognition through a clinical collaboration with Roche, evaluating its combination with atezolizumab for DLL3-expressing solid tumours, including small-cell lung cancer (搜索).
Dr Fang explained the rationale behind trispecific development: "While the TCE modality achieved definitive clinical validation through the approval of Tarlatamab in 2024, establishing bispecific TCEs as a clinically proven therapeutic approach for solid tumours, they still face several bottlenecks, including tumour antigen escape, insufficient and unsustained T-cell activation, T-cell exhaustion, and suboptimal selectivity leading to off-tumour toxicities."
Trispecific antibodies overcome these limitations by integrating a third functional binding domain into a single molecular scaffold, enabling multidimensional precision immune regulation that dual-target bispecific formats cannot achieve. One of the biggest advantages is their ability to bind multiple tumour-associated antigens simultaneously, helping overcome target antigen loss and tumour heterogeneity—two leading causes of acquired resistance and treatment failure.
Looking ahead, trispecific TCE-driven immunotherapy is expected to reshape treatment across oncology, particularly in refractory solid tumours, and expand rapidly into autoimmune diseases. "The future of immuno-oncology will be defined by smart, precisely engineered multispecific TCEs," concluded Dr Fang.