The nature of autoimmune diseases lies in the immune system's failure to distinguish "self from non-self," mistakenly attacking the body's own normal cells and tissues, thereby triggering a persistent inflammatory response. Such diseases exhibit two prominent characteristics:

First, the patient population is vast, with a global prevalence rate of 5%–8%. Among these, key indications such as atopic dermatitis, asthma, and chronic obstructive pulmonary disease (COPD) each affect tens of millions of patients. Second, the disease course is prolonged, requiring patients to undergo long-term medication to manage symptoms, which in turn creates a substantial market space.

According to Future Market Insights, the global autoimmune drug market is projected to grow to $226.2 billion by 2035. Notably, the growth rate of China's autoimmune market far exceeds the global average, with the country's autoimmune drug market expected to expand to $26.3 billion by 2032, boasting a compound annual growth rate as high as 23.3%.

However, behind this vast market, existing treatment options still face significant shortcomings: traditional monoclonal antibody drugs often target a single pathway, making it difficult to cover the complex network of immune-inflammatory signaling; some patients respond inadequately to current therapies or develop drug resistance; and there remains room for improvement in the convenience and safety of long-term medication use.

For example, the commonly used anti-IL-4R monoclonal antibody in clinical practice, while effective in treating atopic dermatitis and asthma, still leaves some patients unable to achieve ideal therapeutic outcomes. Additionally, issues such as higher dosing frequency and elevated eosinophil counts in certain patients persist.

The immense market potential and unmet clinical needs provide broad opportunities for the development of bispecific antibodies. Although the current bispecific market remains largely dominated by oncology, the autoimmune field is poised to emerge as the next major arena to capitalize on this technological dividend.

Bispecific antibodies enable precise and simultaneous blockade of two independent or overlapping pathogenic pathways, or target both immune cells and inflammatory mediators in a single intervention, thereby achieving more comprehensive and profound immune regulation. This "dual blockade" strategy holds promise for overcoming the limitations of monoclonal antibody therapies, offering patients superior and more sustained clinical remission.

Wu Shenglong, CBO of Quanxin Biotech, previously noted in an interview: "The autoimmune market is vast, with blockbuster drugs frequently emerging. It stands as the second-largest global pharmaceutical market after oncology, yet significant unmet needs remain. However, competition in the autoimmune field is intense, with substantial pipeline overlap. Long-acting bispecific antibodies for autoimmune diseases represent a differentiated strategic approach and are the optimal choice for reshaping the current market landscape."

Overall, the autoimmune field is developing rapidly, with new targets continuously emerging. According to incomplete statistics, there are 62 target combinations in the global bispecific autoimmune space, over 60% of which are still in the preclinical stage.

The first wave of multinational corporations (MNCs) to recognize this opportunity has already taken action. Major pharmaceutical giants, including Johnson & Johnson, Sanofi, and Roche, have strategically invested in the autoimmune bispecific antibody space. The cumulative value of mergers, acquisitions, and related drug transactions in this area has exceeded $8.15 billion (approximately RMB 59.1 billion, based on 2024 data).

Specifically, these pharmaceutical giants are expanding their product portfolios and advancing therapeutic iterations by developing bispecific antibody pipelines. Among these, bispecific products targeting validated targets such as CD3, TSLP, and interleukins have become a core focus in the new drug R&D strategies of many MNCs.

Turning our attention to the domestic landscape, innovative Chinese companies such as Quanxin Biotech, KeyMed Biosciences, Akeso Inc., and Huashen Zhiyao are actively participating in the global arena of competition and collaboration. Together, they have driven the BD (business development) boom in autoimmune bispecific antibodies in 2025.

Among them, Quanxin Biotech has "scored three consecutive wins" with its three long-acting autoimmune bispecific antibody pipelines, partnering with entities ranging from NewCos and MNCs to overseas biotech companies. This fully reflects the unanimous optimism of the international market toward autoimmune bispecific antibodies.

In these transactions, the combination logic behind popular targets is worth exploring in depth.

Among them, TCE (T-cell engager) bispecific antibodies dominate the landscape. For instance, KeyMed Biosciences and InnoCare's CD3×CD20 bispecific antibody ICP-B02, as well as the BCMA×CD3 bispecific antibodies developed independently by Harbour BioMed and Zhixiang Jintai, efficiently and durably eliminate pathogenic B cells by redirecting cytotoxic T cells. This provides a novel weapon for treating patient populations resistant to traditional therapies in diseases such as SLE and multiple sclerosis.

TCE technology has garnered significant attention from global pharmaceutical companies and has become a hot topic in the overseas expansion of Chinese innovative drugs. By 2025, the cumulative BD transaction value related to global TCE pipelines has exceeded $3.1 billion, highlighting the broad recognition within the industry of TCE technology's immense potential in the autoimmune field.

At the same time, bispecific combinations centered around TSLP are also a major focus of R&D efforts. For example, Quanxin Biotech's QX031N, developed in collaboration with Roche, targets TSLP and IL-33, while its QX027N, developed with Windward, targets TSLP and IL-13.

Regarding this, Wu Shenglong explained in a previous interview: "TSLP's mechanism of action is relatively broad-spectrum, applicable in both respiratory and dermatological fields. For many companies, whether developing bispecific antibodies or exploring combination therapies, TSLP serves as a critical cornerstone."

TSLP plays a key role in the onset and progression of various immune diseases. It can activate immune cells such as dendritic cells and T cells, triggering a cascade of inflammatory responses. Combining TSLP with other targets is expected to regulate immune responses more comprehensively and enhance therapeutic efficacy.

IL-13 is another common target, often combined with other cytokines or receptors to form bispecific antibodies. For instance, Johnson & Johnson acquired Proteologix to obtain bispecific antibodies targeting IL-13/TSLP and IL-13/IL-22. IL-13 plays a significant role in Th2-type immune responses and is involved in the pathogenesis of diseases like asthma and atopic dermatitis.

Combining IL-13 with TSLP may simultaneously modulate innate and adaptive immunity, addressing different pathogenic mechanisms of diseases. Pairing it with IL-22 could potentially produce synergistic effects in regulating skin immunity and epithelial cell function, offering new avenues for treating skin autoimmune diseases such as atopic dermatitis.

Myeloid Cell Engagers (MCEs) represent another emerging form of bispecific antibodies. These activate myeloid effector cells like macrophages to phagocytose and clear pathogenic target cells, making them particularly suitable for diseases where macrophage dysfunction or impaired clearance of apoptotic cells contributes to pathogenesis.

For example, Zean Biotech's strategic collaboration with Lilly on developing MCE platforms for autoimmune diseases, as well as Sanofi's $1.9 billion collaboration with Dren Bio for DR-0201 (Dectin-1×CD20), further validate the industry's recognition of the potential of MCE platforms in autoimmune treatment.

Additionally, the value of mature platforms is becoming increasingly evident. Platforms such as Harbour BioMed's HCAb and WuXi Biologics' WuXiBody™ have reached international standards in addressing druggability challenges. Sanofi's renewed collaboration with Huashen Zhiyao also underscores its confidence in the value of its bispecific antibody platform.

However, just as the BD activity for autoimmune bispecific antibodies was heating up, a "cold splash" was unexpectedly delivered.

In the final few working days of 2025, Johnson & Johnson announced the early termination of the global Phase IIb DUPLEX-AD clinical trial for its candidate drug JNJ-5939 in patients with moderate-to-severe atopic dermatitis (AD).

How should we understand the treatment needs for AD? As a condition requiring long-term management, ideal therapy must not only address skin lesion repair and inflammation control but also deliver rapid and sustained itch relief, which is a critical evaluation metric, placing extremely high demands on the overall performance of the drug.

Regarding the reasons for termination, Johnson & Johnson did not disclose detailed specifics, only stating that the "planned interim analysis results did not meet the stringent efficacy criteria we established for advancing the AD clinical development program."

JNJ-5939 is a bispecific antibody targeting IL-4Rα (interleukin-4 receptor alpha) and IL-31 (interleukin-31). This was not developed in-house by Johnson & Johnson but was acquired through its $1.25 billion purchase of Yellow Jersey, a wholly-owned subsidiary of Numab, in 2024, at which point it was in Phase II clinical trials.

From the perspective of target combination design, IL-4Rα is a classic target in the autoimmune field. By blocking the IL-4/IL-13 signaling pathway, it can effectively suppress inflammatory responses and the formation of skin lesions. Drugs targeting this pathway, represented by the "super blockbuster" Dupixent (dupilumab), have already demonstrated efficacy across multiple indications.

Meanwhile, IL-31 is a key pruritogen (itch-inducing factor) discovered in recent years. Its mediated signaling pathway is closely related to itching symptoms in autoimmune patients. Nemolizumab has gained significant attention precisely for its effectiveness in treating itch by targeting this pathway.

The combination of the two was initially expected to achieve "two benefits with one action." However, the failure of the Phase IIb trial not only turned Johnson & Johnson's over-one-billion-dollar BD investment into a loss but also cast a shadow over this "idealized" target combination, even raising questions about the future of the entire autoimmune bispecific antibody field.

On one side lies tens of billions of dollars in capital and expectations; on the other side is the harsh scrutiny of clinical efficacy. Will autoimmune bispecific antibodies truly be able to initiate an "efficacy revolution"?

Looking back at the entire R&D journey of autoimmune bispecific antibodies, failure cases similar to Johnson & Johnson's JNJ-5939 are not uncommon.

Amgen's AMG966 (a TNF-α/TL1A bispecific antibody) faced severe immunogenicity issues during its first-in-human clinical study in healthy volunteers, with anti-drug antibodies (ADA) detected in as many as 98.1% of participants, prompting Amgen to terminate the project.

Prior to this, Sanofi's IL-4/IL-13 bispecific antibody encountered similar setbacks. Beyond JNJ-5939, Johnson & Johnson also discontinued the development of two TNF-α/IL-17 bispecific antibody pipelines due to ADA issues.

Then there is IGM Biosciences, which underwent significant layoffs in early 2025. Its CD20/CD3 bispecific antibody (IGM-2323), after shifting focus from oncology to autoimmune diseases, was ultimately abandoned when Phase Ib trials for rheumatoid arthritis and systemic lupus erythematosus failed to achieve the anticipated B-cell depletion effect.

These successive cases collectively reveal a stark reality beyond mechanistic exploration in the field of autoimmune bispecific antibodies: the path to clinical translation is far more complex than theoretical assumptions.

First, the inflammatory network in autoimmune diseases is intricate, often featuring compensatory pathways. As a result, seemingly perfect target combinations may not achieve the ideal "1+1>2" synergistic effect in the human body.

Second, immunogenicity remains a long-term "Sword of Damocles." Autoimmune patients often require prolonged medication, placing stricter demands on drug safety. Bispecific molecules, with their two distinct antigen-binding sites, inherently carry a higher risk of immunogenicity issues.

When bispecific antibodies enter the human body, the immune system may recognize them as foreign entities, triggering an immune response. This can not only neutralize the drug's efficacy, leading to treatment failure, but also cause severe adverse reactions such as allergic responses or cytokine release syndrome. Despite efforts to mitigate these risks through humanization, optimized design, and other strategies, no completely reliable solution exists yet, posing a significant concern for long-term medication safety.

Third, manufacturing processes and costs represent a high barrier to industrialization.

The production of bispecific antibodies involves more complex processes such as expression, purification, and correct assembly. Fluctuations at any stage can impact yield, purity, and quality stability, leading to high production costs and challenging process development. Achieving large-scale, high-quality, and sustainable commercial production remains a series of engineering hurdles to overcome.

Finally, clinical development strategies themselves face scrutiny.

Designing clinical trials that can scientifically and effectively evaluate the unique and complex mechanisms of bispecific antibodies is a critical challenge. This includes selecting appropriate controls, endpoints, dosing regimens, and managing potential drug interactions. Inadequate clinical designs may fail to demonstrate the true value of a drug or even lead to premature misjudgment of promising candidates.

Therefore, the "cold water" poured by Johnson & Johnson and others injects much-needed rationality into an overheated field. Autoimmune bispecific antibodies must confront the harsh realities of immune network complexity, long-term safety, and process feasibility.

This path of innovation is destined to be challenging. As competition shifts from early-stage target exploration and capital frenzy to a "deep-water zone" where robust clinical data speaks volumes, true breakthroughs will continue to hinge on a profound understanding of disease mechanisms and rigorous validation of clinical value.