Pharmaceutical industry in China grows very fast recently. China likely plays an increasingly important role in the international pharmaceutical arena. “Fast-follow is a common strategy for many companies, but very few are attempting first-in-class biologics. At Huaota, we aim for rapid development of novel biologics targeting cancer, autoimmune diseases and inflammatory diseases” Said Dr. Xiangyang Zhu, CEO of Shanghai Huaota Biopharmaceutical Co., Ltd (“Huaota”). He has returned to China from US for more than 8 years, and has clearly felt the changes in the domestic pharmaceutical industry. He also said that there is still a gap between China and the developed countries in fundamental and translational research. There is a laco of deep mechanistic understanding of target candidates to support the translation of science from laboratory to clinical application. The strong cooperation between universities and enterprises has not been fully built. These are the key elements of pharmaceutical industry that need to be improved soon.

Dr. Zhu has worked in world leading pharmaceutical companies for many years, leading and participating in the development of more than 20 monoclonal antibody and bispecific antibody projects. He is the leader and inventor of Risankizumab in the early phase. After returning to China, he has been serving as the general manager of Huaota Biopharm and is in charge of the global biopharmaceutical research and development.

Huaota Biopharm is a subsidiary of Huahai Pharmaceutical. Since its establishment in 2013, it has inherited the technical advantages and rich experience of Huahai Pharmaceutical in the field of medicine. Under the leadership of Dr. Zhu, an integrated biological drug R&D platform and system have been established, covering antibody discovery, CMC, pilot test, clinical trial, registration, commercial production, etc. Huaota Biopharm has built multiple product pipelines of more than 20 projects focusing on cancer and autoimmune disease, and 7 are in the clinical stage.

Since the concept of bispecific antibody been proposed in 1960, many pharmaceutical companies have developed different technological platforms to develop bispedific antibody with different structures, but only four bispecific antibodies, Removab, Blincyto, Hemlibra and Rybrevant, have been launched on the market. This paucity in bispecific antibody on the market is mainly due to the multiple challenges in the development of bispecific antibodies. "For example, how is the pharmacodynamics/safety balance after the two targets are superimposed or overlapped? No matter how the bispecific antibodies are designed, they are artificial structures. Most of the failures of the bispecific antibodies are due to the inability to satisfy CMC." Dr. Zhu said, "Huaota designs symmetrical dual targeting Ab, and we will start to pay attention to and solve these difficult problems at an early stage, so the expression of our bispecific antibodies can be similar to monoclonal antibodies.”

Thanks to the deep understanding of the difficulties in the development of bispecific antibodies, Huaota Biopharm has overcame many challenges in development of bispecific antibodies. HB0025 is the Huaota’s first bispecific Ab, designed to bind PD-L1/VEGF. It has been granted with global patents and represents the first anti-PD-L1/VEGF bispecific antibody that has been approved by both China and U.S. administration for clinical study. Phase I clinical trials are currently underway in China and U.S..

In addition, inspired by the positive results of the Phase III clinical study of Roche's Tiragolumab combined with Atezolizumab in the first-line treatment of PD-L1 positive metastatic non-small cell lung cancer, Huaota Biopharm has develoed a anti-TIGIT/PD-L1 bispecific antibody, HB0036, which has shown high affinity binding to targets. This project is expected to be granted IND in Q4 of this year.

HOT-1030 is a monoclonal antibody designed to bind CD137 for treatment of advanced malignant solid tumors. Preclinical data shows that its antitumor activity is stronger than Utomilumab with good safety. It has been approved for clinical trials by NMPA on September 25, 2020, and currently it is in Phase I clinical trials. CD137, also known as TNFRSF9 or 4-1BB, is a member of the tumor necrosis factor (TNF) receptor family, mainly expressed in activated T cells, NK cells and dendritic cells and other tumor-associated immune cells. It has been merging as a novel immune checkpoint following PD-1/PD-L1.

In autoimmune area, Huaota Biopharm developed its own anti-IL-17A antibody HB0017, targeting implications like psoriasis, ankylosing spondylitis and psoriatic arthritis. Recently HB0017 has completed Phase I clinical trial in New Zealand and Phase IB clinical trial has been launched in China. Currently, there are two IL-17A monoclonal antibodies reach the market worldwide, Secukinumab (Novartis) and Ixekizumab (Eli Lilly), which have shown great market potential.

In addition to bispecific antibodies, antibody-drug conjugates (ADCs), which combines small cytotoxic molecules with high-specificity monoclonal antibodies, have significantly improved safety and efficacy compared to traditional chemical and biological drugs. Therefore, ADC has been considered the new opportunity in biopharmaceutical industry. In the past decade, ADC devopment was booming. Increasing number of indications have been granted for various ADCs. A number of ADC products have shown excellent clinical results. Since 2009, 12 ADCs have been approved by FDA and other administrations (including Disitamab Vedotin For Injection, made by a Chinese company), and more than 80 others are in active clinical studies. Among them, Adcetris and Kadcyla have become "blockbuster" drugs, with sales of US$ 1.081 billion and US$ 1.572 billion respectively in 2019.

“Small molecule drug has great efficacy but high toxic. The lack of specificity means that it attacks both cancer and normal cells after injection.” said Dr. Zhu. Using antibody as a carrier, ADCs binds to a target antigen on the cancer cell, while the stable linker (stick antibody and small molecule together) enabls the control of precise cytotoxic agent delivery into target cells, so it is called a biological missile. He also emphasized that the concept of ADC is very attractive, but the process is quite complicated, and the stability is a major problem. “ADC is generally unstable in vitro, and the drug stability test requires long time. Therefore, ADC drugs must be freeze-dried, unlike macromolecular drugs that can be made into liquid formulation.

"In addition, the linking method between antibody and small molecule drug is also a major challenge for ADC drug development. If the batch-to-batch stability is not ideal, it would be difficult to make a successful ADC.” Dr. Zhu added. Huaota has also started its ADC program, focusing on the novel target and unmed medical need.

Dr. Zhu said that PD-1 is a once-in-a-century target, which has numerus advantages, such as wide indications, market-proven clinically appliations and low risk. Pharmaceutical companies are crowded in the development of PD-1 antibotides. Therefore, numerous PD-1 antibodies have crowded the Chinese market. Dr. Zhu believes that this phenomenon will gradually improve in the post-PD-1 era. With the discovery of novel immune targets, research on these novel targets will follow. At present, some companies have begun to invest these new trgets. In addition, due to the limited efficacy of single-drug therapy for tumors, it has become a trend to obtain better therapeutic effects by combining antibodies with antibodies and/or small-molecule drugs, that is, the concept of super antibodies. “Generally speaking, the future of biopharmaceutical will be like “hundreds of flowers blooming”, and innovation and quality will win out.”