Dr. Zhan Yifan of Huaota Bio: Bispecific Antibody Combination for Targeted Treatment of Fibrosis and Chronic Inflammatory Diseases

Recently, the 7th Antibody China and ADC Drugs In-depth Focus Summit was held in Shanghai. This summit covers the frontier dynamics in the field of antibody drug and ADC drug research and development, and tracks the latest clinical progress, aiming to break the industry's closed loop, promote innovative and diversified development, and facilitate the healthy development of the entire industry chain.

At the meeting,Dr. Yifan Zhan, Chief Scientist of Shanghai Huaota Biopharmaceutical Co., Ltd., gave a speech on "Combination Application of Antibodies Targeting Fibrosis and Chronic Inflammatory Diseases."

Huaota Biopharmaceutical was established in September 2013 as a subsidiary of Zhejiang Huahai Pharmaceutical Co., Ltd. Since its inception, Huaota has consistently focused on innovation and development, building a comprehensive integrated biologics R&D platform and system, including monoclonal antibodies, bispecific antibodies, fusion proteins, and ADC drug discovery platforms, as well as pilot-scale GMP-compliant active pharmaceutical ingredient and formulation platforms.

At the same time, the company has a rich product pipeline, covering major disease areas such as oncology, autoimmune diseases, and ophthalmic diseases. It currently has over 20 projects under development, several of which have entered the clinical research stage, with clinical trials being conducted in the United States, New Zealand, and China.

This article compiles the highlights of Dr. YiFan Zhan's speech:

Currently, Huaota has developed multiple bispecific antibody products in the oncology field. Among them, the anti-tumor project HB0025 is a bispecific antibody fusion protein targeting PD-L1/VEGF, which has been in clinical trials for three years. In addition to focusing on the application of bispecific antibodies in the oncology field, Huaota also values their use in non-oncology areas and has laid out plans for their application in autoimmune diseases, chronic inflammation, and fibrosis. The impact of these diseases on human health is no less significant than that of tumors.

According to Dr. Yi Fan Zhan, many autoimmune diseases can be controlled during their progression, but there is a cost to that control. For instance, systemic lupus erythematosus (SLE) is primarily treated with glucocorticoids, which need to be maintained at high doses, leading to multiple side effects for patients. Therefore, it becomes essential to seek more innovative therapies that offer better efficacy and higher safety. Antibody drugs hold significant promise in this regard.

Taking Sanofi's Dupilumab as an example, the drug has been approved for multiple autoimmune indications, with global sales reaching $8.681 billion in 2022. Sales continued to rise strongly in 2023, reaching $11.7 billion. Sanofi expects Dupilumab’s sales to reach approximately €13 billion in 2024. This indicates that antibody drugs can unleash greater therapeutic potential in the autoimmune field.

Currently, in the fields of autoimmune and inflammatory diseases, most targets are still cytokine-based because they involve interactions between immune cells and signal transduction. Well-known targets include TNF and IL-17. Looking back, when TNF antibodies first emerged, no one believed they could effectively treat complex immune-mediated diseases. Many companies initially focused on diseases like sepsis, but the actual outcomes were not satisfactory.

Now, more antibody drugs for treating autoimmune diseases are coming into view. For instance, generalized pustular psoriasis is a rare disease with a mortality rate of about 10%, and effective treatment drugs are needed. Currently, BI's Pesoletuzumab has been approved and has entered China.

Huaota also focuses on generalized pustular psoriasis. Its product HB0034 is a humanized IgG1 (Immunoglobulin G1) type monoclonal antibody targeting IL-36R, which can specifically bind to IL-36R and block the signaling of the IL-36 inflammatory pathway.Currently, HB0034 Injection (anti-IL-36R monoclonal antibody) has received orphan drug designation from the U.S. FDA for the treatment of Generalized Pustular Psoriasis (GPP). Huaota will strive to complete this key clinical pipeline this year and advance its submission for market approval next year.

Although antibody drugs have opened up new application scenarios in the autoimmune field, many issues still remain. One such problem is that these cytokines currently show good efficacy only for single rare diseases. When targeting more complex diseases caused by multiple factors rather than a single cytokine, the effect of a single anti-cytokine drug will be relatively limited. As a result, many complex diseases currently lack effective treatment options.

In the past three to four years, Huaota has been exploring this concept: whether it is necessary to simultaneously block two cytokines to achieve better efficacy for certain complex diseases. Antibody combinations targeting multiple cytokines or bispecific antibodies might be a better choice for treating some complex conditions.

In the field of oncology, developing bispecific antibodies or combination therapies has become standard practice, but there are still many successful attempts lacking in non-oncology fields. The R&D team at Huaota discovered that, under certain circumstances, blocking two cytokines can lead to better outcomes, such as broadly inhibiting type 2 inflammation requiring the dual blockade of IL-4 and IL-13.

Introducing the concepts of bispecific and multispecific antibodies into non-oncological diseases is a key consideration for Huaota.Taking IL-17 and IL-36 as examples, from the perspective of inflammation, the role of IL-17 is greater, but from the perspective of fibrosis, the role of IL-36 may be greater. The interaction between the two may promote diseases related to inflammation and fibrosis. According to in vitro experiments, if both IL-17 and IL-36 are blocked simultaneously, the degree of inhibition of the inflammatory response will be greater. Based on this,Huaota has currently developed a bispecific antibody product HB1734, which targets IL-17A+IL-36R for the treatment of scleroderma and idiopathic pulmonary fibrosis.

Although antibody drugs have bright prospects for application in the autoimmune field, new autoimmune drugs still require further encouragement and support from regulatory agencies.

Dr. Yi Fan Zhan introduced that in the field of oncology, when applying to the CDE for bispecific or multispecific antibody projects, there usually wouldn't be much negative feedback. However,For new drugs for autoimmune diseases, on the one hand, the CDE supports this kind of innovation, but it also sets very high requirements, including safety and efficacy. This, in fact, is not enough support for pharmaceutical companies.

He believes that for this kind of innovation, safety is the most important aspect, but in terms of efficacy, more precise criteria and support for combination therapies are needed. How to address regulatory challenges during the new drug application process, how to break through the intense competition in the oncology field, meet clinical needs in the autoimmune sector, and achieve true innovation are all worth deep consideration.