Medicilon Interview with Dr. Yifan Zhan | CD73 targeted therapy has ushered in a new dawn, revealing

In the field of immunotherapy, CD73, an immune regulatory molecule, has attracted much attention in recent years.  As an important component of the tumor microenvironment, CD73 plays an important role in regulating immune responses, inhibiting immune cell activity, and promoting tumor growth and angiogenesis.  Targeted therapy against CD73 has become a target pursued by researchers.  Recently, the ADC project HB0052 of Shanghai Huaota Biopharmaceutical Co., Ltd. (hereinafter referred to as "Huaota") was approved by the FDA to enter clinical trials.

Huaota has long been focused on the research, development and production of new biological drugs in the fields of tumors, autoimmune diseases and fundus lesions.  The company has a rich product pipeline and currently has more than 20 research projects, many of which have entered the clinical research stage and are undergoing clinical trials in the United States, New Zealand and China.  What competitiveness does Huaota have in the CD73 field? What are the new highlights of future pipeline deployment?

With these questions, Shanghai Medicilon Inc. (Medicilon) had the honor to interview Dr. Yifan Zhan, Chief Scientist of Huaota.  Dr. Zhan once worked at the Walter and Eliza Hall Institute of Medical Research in Australia and has been engaged in research in the field of cellular immunity for a long time. He has accumulated rich experience in immune cell activation, differentiation, survival, cell interaction, and the production of cytokines and antibodies.  Currently, at Huaota, he is responsible for promoting the selection of new targets for biological macromolecules, the design of new antibodies, and the construction of antibody drug technology platforms.  Let’s have a fruitful discussion with Dr. Zhan to share the Huaota Biotech’s research process and future prospects in the field of CD73.

Q1

Medicilon: First of all, congratulations on HB0052 being approved by the FDA to enter clinical practice. As an ADC with a First-in-Class innovative immunosuppressive target, what breakthrough significance does HB0052 have for Huaota Biotech?

Dr. Zhan: HB0052 is of great significance to Huaota.  This is Huaota's first ADC project, marking that the company has successfully established an antibody conjugate drug research and development platform and opened up a complete path from early research and development to IND filing.  This laid a solid foundation for the company's subsequent development of more ADC projects.  Currently, Huaota is actively developing bispecific antibody ADCs and dual-payload ADCs, hoping to achieve more breakthroughs in the ADC field.  In addition, HB0052 has great potential to become a new generation of tumor treatment drugs.  As a third-generation antibody drug conjugate (ADC) targeting the CD73 antigen, it can simultaneously exert the antibody-mediated immune system regulation function and the killing function of toxic small molecules on tumor cells, and has a synergistic anti-tumor effect.  Preclinical animal model studies have shown that HB0052 has excellent anti-tumor efficacy, long half-life and satisfactory pharmacokinetic properties.  Toxicology studies also show that HB0052 is safe and well tolerated.  Therefore, Huaota is very pleased that HB0052 has been approved by the FDA to enter clinical trials.  Next, Huaota will apply for IND at CDE. During this process, we also thank Medicilon for its help in the project.

Q2

Medicilon: CD73 is an emerging tumor immune target. Huaota Biotech has taken a unique approach to break through the blue ocean of CD73. One pipeline is the world's first CD73-targeted compound preparation HB0045 and the other pipeline is the CD73-targeted ADC drug HB0052.  Do you think it is possible for the CD73 pipeline being developed by Huaota Biotech to overtake others in the future?

Dr. Zhan: Huaota has made diversified layouts and considerations for CD73.  As a potential immunotherapy target, CD73 has attracted many companies around the world to invest in research and development.  Although companies like AstraZeneca are making faster progress than us, no drug targeting CD73 has yet been approved for marketing. This is a time challenge and opportunity we face.

CD73 is highly expressed in many tumor cells.  Although it is not yet a mature target, we believe it has the potential to become an ADC target.  Therefore, we launched the HB0052 project, hoping that it could maintain the immunomodulatory effect of CD73 and target highly expressed tumors to achieve dual tumor suppression effects.  In addition, considering the particularity of CD73, there are two forms: soluble and membrane.  Most monoclonal antibodies have some drawbacks.  In order to overcome these problems, the cocktail compound antibody HB0045 we developed uses dual-epitope targeting technology, which to a certain extent avoids the shortcomings of other projects.  Our test results show that HB0045 has excellent enzyme activity inhibition and immune restoration effects, and has better tumor inhibitory effects than other control antibodies.  Unlike “miracle drugs” such as PD-1, we believe that CD73 antibodies may not achieve the same breakthrough.  Therefore, it is crucial for us to find the beneficial population, which is also a key direction to realize the value of CD73-targeting antibodies.  In recent years, we have laid out biomarkers to guide appropriate indications and patient screening, and to evaluate drug efficacy through patient stratification.   In short, I believe that our two CD73 products may have some advantages, and I hope to have the opportunity to develop beyond the competition.

Q3

Medicilon: What are the key challenges to realize the full potential of Huaota's products in the oncology and autoimmune fields?

Dr. Zhan: I think the challenges mainly lie in two aspects.  Our President Xiangyang Zhu has always been committed to creating products with differentiated advantages, because differences alone are not enough to make us stand out.  We have put a lot of effort into this.  Just like our project on CD73, we must ensure that it has advantages in real data and surpasses similar research projects.

In addition, we have also made breakthroughs in the field of autoimmunity. We are the first company in China to launch IL-36R monoclonal antibody to treat rare diseases.  Although the clinical trial results are very impressive, for Huaota, how to commercialize it and expand its indications are still huge challenges.  We are exploring its potential by trying methods such as dual targets.  As a company that is not yet public, we need to prove the value of our product to the outside world.  We know that the development cycle of new drugs is long, the success rate is low, and the cost is high. There are still great limitations in relying solely on our own resources and strength.  Therefore, we have chosen to expand investment in BD financing and look for more collaboration opportunities with the outside world, such as through external licensing and joint development, to explore the full potential of Huaota in the field of tumors or autoimmunity.  We believe that through our efforts with our partners, we will be able to make more contributions to public health.

Q4

Medicilon: Several product lines of Huaota have entered the mid-to-late clinical stage, and currently have BIC and FIC potential drugs.  So in the next few years, what milestones are expected to be achieved in Huaota’s R&D pipeline?

Dr. Zhan: In the next few years, I have full confidence in the development of Huaota.  First of all, we are about to usher in the first domestic key clinical trial of anti-IL-36R monoclonal antibody HB0034 for the treatment of generalized pustular psoriasis (GPP), and are expected to submit a BLA application in 2025, which is expected to become the first innovative drug we apply for.  In addition, we recently published excellent clinical data on the anti-IL-17 monoclonal antibody HB0017 in a top journal.  We believe it has the potential of BEST IN CLASS, with a long half-life and superior efficacy, which is expected to enter the critical phase III clinical study in Q1 of 2024.  In the field of oncology, we have high hopes in PD-1/VEGF bispecific antibodies.  While many competitors are one step ahead, we hope to be able to move faster and enter critical development stages in the coming years, including through combinations.  In addition, ADC drugs will also enter a critical stage of development.

It has been about three years since I joined Huaota.  We are committed to developing areas with unmet needs, such as new drug candidates for fibrotic and chronic inflammatory diseases, and have achieved impressive preclinical results.  We expect these projects to enter clinical trials in the next few years because Huaota's current product line is very rich.  Despite the challenges we face, we are confident about our prospects.

Q5

Medicilon: Currently you are responsible for the selection of new targets for new macromolecule drugs at Huaota Biotech. Can you share the areas of new targets that you are currently paying more attention to?  Or after PD-1/L1 inhibitors, where do you think the next breakthrough in the field of tumor immunotherapy may appear?

Dr. Zhan: Facing the challenge of new macromolecular drugs, we often think like a blind man trying to feel the elephant. Before success, I can only talk about the fields I am familiar with.  The targets of macromolecule drugs are not limited to the tumor field, but also actively carry out many attempts in non-tumor fields, such as research on diseases of fibrosis or chronic inflammation.  In fact, 45% of human deaths are related to fibrosis-related diseases.  However, currently, there are relatively few truly effective molecular drugs in this type of disease, and only individual small molecule drugs are available.  Therefore, we have already begun to deploy in this area.

My philosophy is that targets such as IL-17 have the potential to be “single miracle drugs”.  However, in the face of some complex diseases, it may not only be necessary to have a single target, but multiple targets need to be targeted at the same time.  Of course, in the field of oncology, we are also paying close attention to the development of PD-1, and the current focus has turned to ADCs.  However, ADC also faces a challenge, that is, we cannot only focus on saturated R&D targets, but need to find some new targets.,  Of course, new targets are relatively more challenging, such as tumor-specific antigens.  Although many people are conducting research in this direction, how to truly achieve targeted therapy of tumor-specific antigens is still a problem to be solved.  Therefore, we are also committed to improving the resistance problem of ADC drugs, including primary resistance and later-developed resistance.  We have some innovative ideas and new platform technologies to solve these problems, such as coupling technology and diversity of small molecules, which may also provide us with a new research perspective.  Currently, only 20% to 30% of the population benefit from PD-1-based immunotherapy.  In fact, many tumors are not sensitive to all immunotherapy approaches.  My personal research background has led me to focus more on how to improve the tumor microenvironment.  There are currently many people working in this field.  We focus more on how to improve the tumor microenvironment, including inhibiting tumor-related immunosuppressive cells and breaking through the barriers of fibrotic tumors.  Why is pancreatic cancer so difficult to treat?  Because it is like a tumor surrounded by fibrosis, immunotherapy alone cannot penetrate it.  Therefore, I think improving the tumor microenvironment should be a worthy direction.  Although it is still early days in these efforts, I am optimistic about the future of these advances.

Q6

Medicilon: In your research, there is long-term research on GM-CSF regulating the development and function of dendritic cells and macrophages, and there are also papers published on related results.  What progress do you think can be achieved by using GM-CSF to regulate the development and function of dendritic cells and macrophages in the treatment of immune-related diseases?

Dr. Zhan: I have been researching in Australia for more than 30 years, focusing on exploring the role of immune cells in physiology and pathology, especially macrophages.  Cytokines are key to controlling immune cell growth and function.  Among them, GM-CSF was a cytokine discovered in Australia by a late outstanding scientist and his team.

Initially, I was fascinated by the role of cytokines in hematopoiesis during bacterial infection.  But as my research deepened, I gradually discovered that cytokines not only control the production of immune cells, but also have a profound impact on their functions.  Therefore, I spend a lot of time studying how cytokines promote macrophage and dendritic cell function.  As research continues, we have discovered that the effects of cytokines sometimes have the opposite effect and even continue to suppress immune cells.  Therefore, in some experimental stages, by inhibiting GM-CSF, we can effectively reduce tumor metastasis.  However, this double-edged sword also makes it more difficult for us to find the balance point of signaling in various diseases, and we need to continuously explore how to achieve better therapeutic effects by regulating the effects of cytokines.

Q7

Medicilon: You have published more than 100 academic papers in international journals, and have transitioned from academics to the role of company R&D leader.  How do you see the relationship between academic and professional leadership roles?

Dr. Zhan: This is also a question I often reflect on.  I believe that my past 30 years of basic scientific research have fully prepared me for my current new role.  Especially in the environment where China's biopharmaceutical industry is gradually moving from generic drugs to independent innovation, my background in immune cell research is exactly in line with the needs of this era and matches the positioning of Huaota, allowing me to have such a new role.  However, I still do not consider myself a mature business leader because I have been overseas for a long time and am still in the process of adapting to the changes in the current workplace.

Fortunately, our highly acclaimed CEO, Dr. Xiangyang Zhu, has extensive experience in large molecule drug development and can lead our team to face and overcome various challenges.  When we face the era of innovation, we will embark on untrodden roads with our team and explore the unknown world together.  I am confident that I can accomplish this mission.

About Huaota

Huaota Biopharmaceutical is a new biological drug R&D enterprise focusing on independent development and focusing on the world.  Focusing on the research and development of new biological drugs in the fields of tumors, autoimmune diseases, and fundus lesions, there are currently 11 projects in the clinical stage: including the first Chinese developed IL-36R monoclonal antibody for pustular psoriasis (rare disease) that is about to enter the critical phase II; the PD-L1/VEGF dual antibody has been in clinical phase II and has observed positive signals in endometrial cancer and renal cancer; and core projects such as the first CD73-ADC with dual killing effect targeting refractory tumors such as pancreatic cancer.

Huaota Biopharmaceutical is currently actively looking for domestic and foreign partners to jointly promote and develop, and looks forward to providing high-quality and high-level biopharmaceuticals to the global market to meet the needs of patients for biopharmaceuticals with high accessibility and affordability, and implement the vision of innovation to change the world!