According to statistics, the global bispecific antibody market size will reach US$13 billion in 2024, among which the combined sales of cardunili and ivocizumab of Chinese pharmaceutical company Kangfang Bio are expected to exceed US$300 million, leading the trend of tumor immunotherapy bispecific antibodies.

Recently, Kangfang Bio has once again expanded the application of bispecific antibodies to another explosive field - the autoimmune field.

Kangfang Bio announced that its world's first non-tumor bispecific antibody IL-4Rα/ST2 (AK139) IND has been accepted, targeting the large market of respiratory and skin autoimmune diseases.

Challenge the 100 billion market

Autoimmune diseases refer to diseases in which the body's immune system malfunctions, causing the body to attack its own tissues. Currently, there are 100 different types of autoimmune diseases known, affecting about 7.6% to 9.4% of the world's population. Among them, atopic dermatitis, asthma, COPD, psoriasis and other diseases have a prevalence of more than 100 million people. Moreover, most of these diseases are chronic diseases, and patients take medication for a long time, so there is a huge demand space.

In recent years, with the understanding of diseases, macromolecular biological drugs targeting inflammatory cytokines, receptors and signaling molecules have developed rapidly, and a number of "super blockbusters" have been born, of which three will have sales of more than 10 billion US dollars in 2024: DUPIXENT, SKYRIZI, and STELARA. The global autoimmune drug market is growing rapidly, with a total scale of more than 100 billion US dollars, and has become the world's second largest drug market after tumors.
In China, after years of accumulation, domestically produced autoimmune new drugs also ushered in an outbreak in 2024. Sipuqibaimab, Celizumab, and Funaqizumab were approved for listing one after another, joining the competition in the 100 billion US dollar market.

However, traditional biologics (such as monoclonal antibodies) often only target a single target (such as IL-4Rα, IL-13 or JAK pathway), but autoimmune diseases often involve complex immune signaling networks and multi-target abnormalities. For example, immune abnormalities in patients with atopic dermatitis (AD) may involve cytokines such as IL-4 and IL-13 at the same time, and a single targeted therapy cannot completely block disease progression. In addition, some rare or complex autoimmune diseases still lack effective therapeutic drugs. Therefore, there is still a great clinical need to develop next-generation immunotherapy drugs.

Killing two birds with one stone, combining two golden targets

Compared with monoclonal antibodies that act on a single inflammatory pathway, AK139 can simultaneously target IL-4Rα and ST2 to achieve dual blockade of IL-4/IL-13 (Th2 pathway) and IL-33 (Th1/Th2 balance regulation). And it has a synergistic effect of targets. Preclinical studies have shown that this synergistic effect can more comprehensively inhibit type 2 inflammatory responses, especially for chronic diseases driven by multiple pathways such as asthma and atopic dermatitis.

IL-4Rα pathway: IL-4 and IL-13 (which share a common receptor, IL-4Rα) are mainly involved in the immune response mediated by type 2 helper T cells (Th2). The type 2 inflammatory pathway mediated by them plays a key role in a variety of immune functions, especially in allergic diseases such as asthma and allergic rhinitis.

Among them, DUPIXENT (duplimab), jointly developed by Regeneron and Sanofi, is a fusion protein targeting this target. The drug has been approved for indications covering atopic dermatitis (AD), asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), eosinophilic esophagitis (EoE), prurigo nodularis (PN) and other skin and respiratory system indications. It was also approved in 2024 as the first biological agent for the treatment of chronic obstructive pulmonary disease (COPD). In 2024, the sales of the drug reached US$14.15 billion, successfully becoming the new "king of drugs" in the field of autoimmunity.

Previously, Kangfang Bio has also developed IL-4Rα monoclonal antibody AK120, which has entered Phase II/III clinical trials. As Kangfang Bio's first dual-antibody drug in the non-tumor field, AK139 also chooses IL-4Rα as one of its targets. It can bind to IL-4Rα with high specificity and block the binding of IL-4Rα to IL-4 and IL-13 and the downstream signaling pathways mediated by it. At the same time, it targets the ST2 pathway, which is expected to cover more patients than the "King of Medicine".

IL-33/ST2 pathway: Interleukin-33 (IL-33) as an early warning factor can bind to its specific receptor ST2, activate downstream signaling pathways, and lead to respiratory, cardiovascular, musculoskeletal and other multi-system inflammatory diseases, playing a key role in both type 2 and non-type 2 inflammation. Studies have shown that IL-33 and its specific receptor ST2 are abnormally expressed in a variety of autoimmune diseases, such as asthma, allergic rhinitis, atopic dermatitis and other respiratory and skin system diseases. Among them, Roche/Amgen's ST2 monoclonal antibody RG6149 has started Phase III clinical research for COPD.

AK139 can specifically bind to ST2 and inhibit IL-33-mediated inflammatory response. At the same time, preclinical studies have shown that AK139 has good bispecific antigen binding activity, and shows a synergistic effect that is significantly better than IL-4 or ST2 single-target antibodies in indicators such as inhibiting the release of inflammatory factors and tissue inflammatory cell infiltration.

At present, there are no antibody drugs that have been launched or are in the process of development in the world that simultaneously target IL-4Rα and IL-33/ST2 pathways. AK139 is expected to become a breakthrough therapy for respiratory and skin system diseases and a next-generation blockbuster drug in the field of autoimmunity.

Kangfang's bi- antibody kingdom Kangfang Bio is famous for its tumor immune bi-antibodies. It first launched the world's first PD-1/CTLA-4 bi-antibody cardunilimab on the market, and then authorized part of the rights and interests of the PD-1/VEGF bi-antibody ivocizumab to go overseas for US$5 billion (US$500 million down payment).

In May last year, Kangfang Bio announced that Ivosimab defeated K drug (pembrolizumab) head-to-head, setting off a wave of research and development of tumor immune dual antibodies.

Its HARMONi-2 (AK112-303) study data showed that Ivosimab monotherapy significantly prolonged patients' progression-free survival (PFS) compared with K drug first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with positive PD-L1 expression, and the hazard ratio (HR) was significantly better than expected.

With these two dual antibodies, Kangfang Bio will achieve profitability for the first time in 2023, and product revenue is expected to grow further in 2024.

The advancement of AK139 reveals its further ambitions.

Relying on the Tetrabody platform, Kangfang has promoted 7 dual antibodies into clinical trials. Previous dual antibody pipelines have focused on the field of oncology, and AK139 is another breakthrough for Kangfang in the field of non-tumor dual antibodies.
At present, the annual sales of Cardunili have successfully exceeded the 1 billion yuan mark. At the same time, Ivosi has also been successfully approved for listing and has shown extraordinary charm on the international stage, which has effectively built a solid barrier for Kangfang in the field of tumor bispecific antibodies. The approval of AK139 for clinical trials marks a key step in the expansion of Kangfang's bispecific antibody technology platform into the field of chronic diseases. If AK139 can verify its advantages in the field of autoimmune diseases, Kangfang Bio will undoubtedly step onto a new level in the journey of BigBiotech and achieve more brilliant achievements.

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