Recently, the multispecific antibody (polyclonal antibody) pipeline has seen explosive growth, with multiple drugs entering the clinical trial stage in quick succession.

Akeso Biopharma's first triple antibody drug AK150 (ILT2/ILT4/CSF1R triple antibody) has received implied approval from the NMPA for clinical trials to treat advanced malignant solid tumors.
Henlius' next-generation TCE quadruple-specific antibody HLX3901 (DLL3 x DLL3 x CD3 x CD28 quadruple-specific antibody) has been approved for IND by the NMPA and is intended for the treatment of advanced or metastatic solid tumors.

The evolution from bispecific antibodies to trispecific and quadrispecific antibodies signifies the beginning of another iteration in the antibody field, bringing both challenges and opportunities to the industry.

01

Pipeline numbers explode

With the rise of molecular biology, the era of targeted therapies against single targets has arrived. Breakthroughs in monoclonal antibody technology have enabled drugs to precisely target single biological targets.

However, due to the complexity of living systems, the inhibition of a single target often fails to address the essence of the disease , such as the drug resistance of tumors and the redundant signaling networks of autoimmune diseases, gradually exposing the limitations of single-target drug development strategies.

Bispecific antibodies and multispecific antibodies that can act on multiple different targets simultaneously have become the key to breaking the deadlock.

Multispecific antibodies are not only characterized by an increased number of targets, but also by their synergistic effect , which enhances treatment efficacy and reduces drug resistance.

In recent years, bispecific antibodies have become a focal point of competition among global pharmaceutical companies. According to PharmaNotes, the total sales of 18 marketed bispecific antibody drugs worldwide reached $17.8 billion in 2025, a year-on-year increase of 34%. Among them, Roche's hemophilia FIX/FX bispecific antibody Hemlibra achieved sales of $6.5 billion in 2025, while the ophthalmic VEGF/Ang2 bispecific antibody Vabysmo also surpassed $5 billion in sales.

Following bispecific antibodies, multispecific antibody drugs that simultaneously target multiple antigenic epitopes, such as trispecific antibodies (tri-antibodies) and tetraspecific antibodies (tetra-antibodies), have also rapidly entered the clinical research stage.

According to data from PharmData, there are currently more than 300 multi-antibody drugs under development worldwide, and the number is increasing year by year, of which 80 have entered the clinical stage.

From the perspective of research and development units, both pharmaceutical companies (MNCs) and biotech companies are actively involved. Large pharmaceutical companies such as Johnson & Johnson and Pfizer have pipelines that have progressed to Phase 3 clinical trials. Meanwhile, biotechnology companies such as Numab, Harpoon (acquired by Merck), Baili Tianheng, and Jiahe Biopharma are demonstrating innovation capabilities, with multiple drug candidates in development.

In terms of treatment areas, oncology, immune diseases, and hematological diseases rank first, while respiratory, infectious diseases, and ophthalmological diseases are also represented.

02

MNC Competition

In terms of R&D progress, four products have entered the late clinical stage and have all been acquired by MNC.

JNJ-79635322 is a BCMA/GPRC5D/CD3 triple antibody developed by Johnson & Johnson.

The drug has been initiated in the Phase 3 clinical trial Trilogy-4, which aims to compare the efficacy of JNJ-79635322 and the anti-BCMAxCD3 bispecific antibody in patients with relapsed or refractory multiple myeloma (RRMM) who have received at least three lines of prior therapy (including proteasome inhibitors, immunomodulatory agents, and anti-CD38 antibodies).

Phase 1 clinical data showed that, with a median follow-up of 15.0 months, JNJ-79635322 (100 mg, Q4W) treated 27 patients (n=27) who had not received BCMA/GPRC5D targeted therapy, achieved an ORR of 100% and a PFS of 12 months in 96.3% of the patients.

PF-07275315 (Tilrekimig) is a triple antibody developed by Pfizer that contains IL-4, IL-13, and TSLP.

These three targets are core drivers of the type 2 helper T cell (Th2) immune response pathway, playing a key role in the pathogenesis of chronic inflammatory diseases such as atopic dermatitis, asthma, and chronic obstructive pulmonary disease (COPD).

In January of this year, Pfizer registered a global Phase 3 clinical trial for the drug to treat chronic obstructive pulmonary disease (COPD). The Phase 3 clinical trial plans to enroll 1,156 COPD patients and is expected to be preliminarily completed in October 2030.

Furthermore, the Phase 2 clinical trial of this drug for the treatment of moderate to severe atopic dermatitis (AD) has yielded positive results. After placebo adjustment, the proportions of patients achieving a ≥75% reduction in eczema area and severity index (EASI-75) at week 16 were 51.9% and 49.4% in the medium- and high-dose groups, respectively, demonstrating its potential to surpass existing standard-of-care biologics. Pfizer expects to initiate a pivotal Phase 3 trial for atopic dermatitis within the year.

Meanwhile, MNC acquired and accelerated its multi-resistance pipeline through mergers and acquisitions and BD.

In January 2024, Merck acquired Harpoon Therapeutics for $680 million, gaining access to a range of TCE products, including the DLL3/CD3/Albumin triple antibody HPN328 (MK-6070).

In May 2024, Merck acquired EyeBio for $3 billion, gaining access to Restoret (EYE103), a quadrivalent trispecific antibody.

This drug can bind to both receptors LRP5 and FZD4, mimicking the function of the natural ligand Norrin and activating the Wnt signaling pathway. Currently, it has entered the pivotal Phase 2b/3 study (BRUNELLO/EYE-RES-102), which aims to evaluate the efficacy and safety of EYE103 (low/high dose) versus ranibizumab (0.5 mg) in treating treatment-naïve patients with diabetic macular edema (DME).

AbbVie is also an active buyer in the multi-antibody field.

In January 2025, AbbVie acquired a GPRC5D/BCMA/CD3 triple antibody SIM0500 from Simcere, with the cooperation amount exceeding US$1 billion.

In July, AbbVie paid a $700 million upfront payment, totaling nearly $2 billion, to acquire exclusive rights to develop, manufacture, and commercialize ISB 2001, a CD3/CD38/BCMA triple antibody drug from IGI Therapeutics SA (IGI), in North America, Europe, Japan, and Greater China.

In December, AbbVie reached a licensing agreement with the domestic innovative pharmaceutical company Zai Lab, obtaining exclusive rights to develop and commercialize ZG006 (Alveltamig), a world-first DLL3×DLL3×CD3 trispecific T-cell binding agent, outside of Greater China.

Zaijing Pharmaceuticals will receive an upfront payment of $100 million, plus up to $60 million in recent milestone payments based on clinical progress and payments related to licensing options; if AbbVie exercises its licensing options, Zaijing is also eligible for milestone payments of up to $1.075 billion.

Currently, Phase 3 clinical trials of ZG006 for the treatment of small cell lung cancer are underway in China . This drug has been designated a breakthrough therapy by the NMPA for recurrent or progressive advanced small cell lung cancer and DLL3-positive neuroendocrine carcinoma, and has received orphan drug designation from the US FDA.

03

Domestic FIC Breakthrough

In this wave of multi-antibody drugs, domestic pharmaceutical companies have taken a leading position, with many drugs possessing the potential for FIC (first in the world) and BIC (best in class).

AbbVie and Zaijing Pharmaceuticals, is the world's first triple antibody targeting DLL3/DLL3/CD3, and also the most advanced triple antibody targeting DLL3 globally.

Baili Tianheng advanced its quadruple antibody drug GNC-038 to the clinical stage, making it the world's first quadruple antibody to be successfully approved for clinical trials. Currently, the company has three quadruple antibody drugs in clinical stages: GNC-038 (PD-L1/4-1BB/CD3/CD19), GNC-039 (PD-L1/4-1BB/CD3/EGFRⅧ), and GNC-035 (PD-L1/CD3/4-1BB/ROR1).

Akeso Biopharma , a leading global bispecific antibody company, recently received implied approval from the NMPA for clinical trials of its first triple antibody drug, AK150, for the treatment of advanced malignant solid tumors.

This drug is a world-first ILT2/ILT4/CSF1R triple antibody developed by Akeso Biopharma based on its AI-powered pharmaceutical R&D platform and Tetrabody multi-antibody technology platform. Preclinical animal models indicate that AK150 has tumor-suppressive effects at all dosage levels, exhibiting a certain dose-response relationship.

Henlius Biotech's HLX3901, a quadruple antibody against DLL3/DLL3/CD3/CD28 developed based on its independently developed innovative TCE platform, has received NMPA approval for an Investigational New Drug (IND) and is intended for the treatment of advanced or metastatic solid tumors.

HLX3901 is a next-generation T-cell connector that, through ingenious molecular design, combines sustained and specific T-cell activation, targeting tumors with low T-cell infiltration, and significantly reducing cytokine release syndrome (CRS), aiming to overcome the major obstacles of first-generation TCEs in solid tumor treatment. Preclinical studies have shown that HLX3901 exhibits superior cytotoxicity under conditions of low target-to-cell ratio.

04

Conclusion

Despite the fact that the development of polyclonal antibodies still faces multiple challenges, including molecular complexity, drugability, safety, and manufacturing processes, no triple or quadruple antibody drugs have been approved for marketing yet.

However, the shift from single-mechanism, synergistic approaches to drug development is a major trend in current drug research. ADCs and bispecific antibodies have demonstrated the potential of this direction. In the future, multispecific antibodies such as triple and quadruple antibodies are also expected to emerge as the mainstream treatment option for the next generation of diseases.

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