Have multi-antibodies started to be "liquidated"?
Highly anticipated multispecific antibody drugs (tri-specific and above) are undergoing a round of re-evaluation.
In the latest prospectus of Baili Tianheng, the three tetra-specific antibody products for solid tumors previously deployed by the company have been removed, leaving only one tetra-specific antibody product targeting autoimmune diseases.
Multispecific antibodies used to be one of the R&D directions that Baili Tianheng invested the most in. This pipeline adjustment ostensibly is the company's optimization of resource allocation before listing, but at the IPO stage where results are most needed to be demonstrated, the initiative to reduce the "world's first" tetra-specific antibody projects more likely means that the development potential of the products has not met expectations.
Coincidentally, prior to this, MNCs such as Amgen, Sanofi and Roche also abandoned multiple multispecific antibody projects, with unclear expected efficacy and high safety risks being the main reasons.
As more and more multispecific antibody drugs enter clinical practice, the early conceptual value is being exhausted, and the next stage will be a phase of coexistence of hustle and reckoning.
Multispecific antibodies are still a next-generation therapeutic direction with full potential, but new drug R&D is never about showing off skills. Only products that can truly meet clinical needs can survive this round of elimination.
01
The Retreat of Pioneers
"Led by multispecific drugs, the pharmaceutical industry will usher in the fourth revolutionary wave".
In 2020, Professor Raymond J. Deshaies of the United States put forward this prediction in a paper published in the journal *Nature*.
No one wants to miss the opportunity. Baili Tianheng is undoubtedly one of the earliest and most aggressive enterprises in this field.
As early as 2020, Baili Tianheng launched the GNC038 clinical trial, becoming the world's first tetra-specific antibody to enter the clinic, and successively developed multiple tetra-specific antibody products such as GNC035 and GNC039 relying on the GNC platform. In 2022, Zhu Yi, the chairman of the company, said in an interview with the media that the R&D of penta-specific antibodies had already been started.
Indeed, there is no "most", only "more".
Since diseases are inherently complex and arise from multiple factors and mediators, theoretically, multispecific antibodies have their scientific logic. Just as the essence of bispecific antibodies is to overcome single-target resistance and improve the specificity of tumor killing through synergistic effects.
The purpose of multispecific antibodies is to simultaneously perform multiple functions on a single molecular carrier: tumor cell recognition and anchoring, T cell recruitment, co-stimulatory signal activation, and immune checkpoint blockade. Theoretically, it can realize the synergy of multiple immune pathways to achieve the therapeutic effect of "1+1+1>3", so as to make up for the shortcomings of bispecific antibodies in tumor treatment, such as insufficient T cell activation and limited tumor recognition specificity.
Take the 4-1BB target as an example. Traditional 4-1BB monoclonal antibodies are difficult to balance efficacy and toxicity due to the widespread expression of the target throughout the body; while multispecific antibodies can use the anchoring effect of tumor antigens to limit the activation effect of 4-1BB to local tumor tissues, thereby reducing systemic adverse reactions, which is also a very important theoretical support for the design of multispecific antibodies.
Of course, the boom of multispecific antibodies is also inseparable from the support of industry narratives in the IO 2.0 era. As the trend of PD-(L)1/VEGF accelerating the iteration of monoclonal antibodies is confirmed, pharmaceutical companies including Dalian Biology, Jiahe Biotech, Immuneune and Zelgen have entered the market one after another, hoping to further upgrade and iterate on IO 2.0 therapies, make forward-looking layouts for multispecific antibodies, and even explore six-target candidates.
Many BD transactions have also emerged in the multispecific antibody field. However, when the market expects further progress in this field, Baili Tianheng, the pioneer, has begun a large-scale retreat.
On August 6, Baili Tianheng submitted its listing application to the Hong Kong Stock Exchange for the fourth time. In the latest prospectus, the company has removed three tetra-specific antibody products from its pipeline: GNC-035 targeting CD3/4-1BB/PD-L1/ROR1, GNC-039 targeting CD3/4-1BB/PD-L1/EGFRvIII, and GNC-077 (based on CD3) with undisclosed targets. The oncology multispecific antibody pipeline has been completely abandoned, leaving only GNC-038 targeting CD3/CD19/PD-L1/4-1BB for autoimmune diseases.
In fact, Baili Tianheng had already begun to reduce resource investment in tetra-specific antibody projects before. In 2023, the company adjusted the fund-raising usage plan, reduced the investment in subsequent Phase II/III clinical development of tetra-specific antibodies, and increased investment in directions such as ADCs.
Although the company stated at that time that the existing tetra-specific antibody products had good clinical performance and reducing investment would not affect R&D progress, it now seems that the company may have had the intention to retreat at that time.
02
Practical Dilemmas
Whether it is bispecific, tri-specific or even tetra-specific antibodies, they must prove evidence of further improvement on the existing standard of treatment, either safer, more effective, or more convenient to use, which is the most basic requirement for innovation.
However, in the critical window period of IPO, Baili Tianheng took the initiative to cut down multiple tetra-specific antibody projects with the "world's first" label, reducing its own imagination space, which reflects from the side that the clinical performance of multispecific antibodies is not as good as expected.
This means that compared with the theoretical design full of imagination on paper, the practical dilemmas faced by multispecific antibody R&D are more intractable.
That's true. The first challenge for multispecific antibodies is the uncertainty of efficacy.
Whether it is GNC-035 or GNC-039, both chose the CD3/4-1BB co-stimulatory signal, aiming to enhance the lethality of T cells to tumor cells, and combined with PD-L1 to further relieve immunosuppression, which can theoretically achieve the maximum synergistic effect.
However, in the field of solid tumors, there is obvious heterogeneity, the affinity of single targets such as ROR1/EGFRvIII is limited, and the killing effect of CD3/4-1BB/PD-L1 may not be exerted.
More complexly, multispecific antibodies need to balance the affinity of multiple antibody arms at the same time. The binding strength, spatial structure and pharmacokinetic characteristics between different targets need to be precisely matched. As the molecular weight increases, the tissue penetration of the drug may also decrease. Eventually, the multi-target design may not bring the expected synergy, but increase the development difficulty instead.
Another major challenge is safety.
The co-stimulatory effect of CD3/4-1BB, superimposed with the relief of PD-L1 immunosuppression, causes excessive activation of the immune system, which will lead to side effects such as cytokine storm and autoimmune reactions.
Such side effects have been reflected in similar products. Sanofi's SAR442257 is a tri-specific antibody targeting CD3/CD38/CD28. In a Phase I clinical trial for hematological malignancies, 70.2% (n=33) of patients experienced TEAE, among which CRS was the most common, with an incidence rate of over 55%. Eventually, the development of this drug was terminated due to safety issues.
Baili Tianheng's GNC-039 targets EGFRvIII, a specific target of glioma, but in the complex microenvironment of the brain and the whole body, the immune toxicity brought by CD3 and 4-1BB can easily reach the patient's tolerance limit, which may also be one of the reasons for the pipeline adjustment.
The narrow therapeutic window between efficacy and toxicity means that there is still a huge gap between a large number of multispecific antibody candidate molecules and being successfully developed into drugs.
Of course, Baili Tianheng's shift is not the first adjustment of multispecific antibody drugs. Many MNCs have already carried out re-evaluation on the druggability of multispecific antibodies.
In addition to SAR442257 mentioned earlier, Amgen stopped the drug development of AMG305 targeting CD3/CDH3/MSLN in 2023; in 2025, Roche announced the termination of the R&D of SAIL66, a tri-specific antibody product for solid tumors, and returned the pipeline to Chugai Pharmaceutical, giving the public reason that the R&D progress was slow, which also implies the reality that the clinical benefit is less than expected. Soon after, Chugai Pharmaceutical also announced the termination of the development of this product.
From the successive retreats of MNCs to the pipeline slimming of leading domestic enterprises, the elimination period of multispecific antibody drugs has arrived ahead of schedule.
03
Not Superposition of Quantities
In fact, the industry should have expected this long ago. There have been many clinical failure cases in the bispecific antibody field, and the development difficulty of tri-specific and tetra-specific antibodies will rise exponentially, so it is difficult to simply rely on target stacking to achieve "great results with brute force". After all, new drug development is not playing Lego. The increase in the number of targets does not mean a simultaneous improvement in clinical benefits.
Returning to the essence of druggability, there are several practical problems that enterprises must face. From the perspective of target selection, this pipeline adjustment of Baili Tianheng sends a clear signal: all the eliminated products are multispecific antibodies for oncology, and the only remaining GNC-038 focuses on the autoimmune disease track, with the core anchored at the CD19 target. Compared with solid tumors with extremely strong heterogeneity, it may be easier to find a safe and effective therapeutic window.
Platform technology and industrialization capabilities also determine the survival of multispecific antibody projects.
In order to further expand the therapeutic window and expand the boundary of indications, new generation platform designs are emerging. Among them, the masked strategy TCE (PRO-TCE) that improves tumor selectivity through the precursor activation mechanism is an important direction.
In short, the core idea of PRO-TCE is to connect a "masking peptide" that can be specifically cleaved by tumor-related proteases to the CD3 binding domain and/or TAA binding domain. This masking peptide blocks key binding sites through steric hindrance or weak affinity binding, thereby reducing the affinity of TCE to CD3 or TAA targets, avoiding non-specific activation of T cells throughout the body, and reducing the risk of CRS.
Such a design does not weaken the killing effect. When TCE enters the tumor microenvironment, the locally highly expressed tumor-related proteases will cleave the linker between the masking peptide and TCE, the masking structure will be removed, and TCE with full activity will be released. At this time, TCE can simultaneously bind to the TAA target of tumor cells and the CD3 molecule of T cells, form an immune synapse and trigger T cell-mediated tumor killing.
Baili Tianheng has not given up on multispecific antibodies. It recently announced a patent authorization to upgrade the GNC platform to penta-specific antibodies. The verified target combinations such as EGFR/CD3/HER3/PD-L1/4-1BB show that the platform can theoretically be upgraded to hexa-specific antibodies at most. According to the patent content, the target affinity of the penta-specific antibody is improved, and it shows anti-tumor effects in in vitro tests.
However, the accumulation of targets does not equal the superposition of efficacy. After actually entering the human body, whether it can achieve the expected effect and whether it will cause more serious side effects is still unknown.
In February this year, Roche's innovative drug R&D team published an article titled *The making of multispecific immunoglobulins- a clinical perspective*, which also mentioned that the balance between functional innovation and drug properties is the most important. An overly complex structure not only complicates production and regulatory approval, but also brings unnecessary risks. Selecting targets and designs according to demand to make "format follows function" is the law that drug R&D must follow.
At the industrialization level, the more functional targets and structural modules the molecule integrates, the higher the difficulty of molecular engineering modification and CMC production and manufacturing. The development of multispecific antibodies generally faces industrialization pain points such as heavy chain-light chain mismatch, isomer impurities, protein aggregation, low expression level, and difficulty in large-scale scaling up.
Of course, process obstacles are more challenges at the implementation level. Many multispecific antibody projects for solid tumors have not yet advanced to the large-scale production stage, and their development has been terminated due to clinical efficacy and safety issues.
In the final analysis, multispecific antibody drugs are still a next-generation therapeutic direction with full potential, but the industry needs to abandon conceptual hype, and all value will eventually return to the drug itself. The multispecific antibody track has bid farewell to the stage of pure conceptual speculation. The aura of FIC and complex and fancy target combinations are no longer the core competitiveness.
Because no matter how exquisite the molecular design is, the criterion for evaluating drugs will never change.
The core of future track competition does not lie in the number of antibody functional arms, but in finding a balance between efficacy, safety and industrialization through rigorous target screening, exquisite molecular structure optimization, and mature platform technology iteration, to meet unmet clinical needs.
This article is from the WeChat official account "Amino Insight" (ID: anjiguancha), author: Sha Xiaowei, published with authorization from 36Kr.