How far is GPCR antibody new drug from 0 to 1?

Archimedes has a famous saying, "give me a fulcrum, I can move the earth." If someone brings this confidence to the pharmaceutical field and says, "give me a target, I can successfully develop a new drug", I'm afraid it will attract a lot of questions For Archimedes, the choice of fulcrum is important; for drug developers, the choice of the right target is also crucial GPCR, the Chinese name "G protein coupled receptor", is the largest membrane protein family in human body, with more than 800 family members At present, there are about 370 targets for ready-made drugs, and it is the largest ready-made drug family protein in human body The diseases involved mainly include nervous system diseases, cardiovascular diseases, cancer, inflammation, etc According to an online article published in Nature Reviews Drug Discovery in October 2017, FDA approved 475 drugs targeting GPCR, accounting for 34% of all approved drugs The success rates of candidate drugs for GPCR protein in phase I, II and III were 78%, 39% and 29%, respectively, which were slightly higher than those developed for other targets [1] However, almost all of the drugs approved by FDA targeting GPCR family proteins are small molecular drugs and low molecular weight peptide drugs Is GPCR antibody medicine a treasure forgotten by the pharmaceutical industry? Obviously not! On May 17, the FDA approved the listing of aimovig (erenumab aooe), the first antibody drug targeting GPCR family protein This McAb developed by Amgen / Novartis targeting calcitonin gene related peptide (CGRP) not only fills the gap of GPCR antibody drugs in the U.S market, but also is analyzed by optimists that the peak sales volume can exceed 10 billion US dollars An article published online in nature reviews drug discovery last July showed the development prospects and market opportunities of GPCR antibody From this review, the reporter found the name of a Chinese bio innovative drug enterprise, Gmax biopharm [2] For this reason, the reporter made a special trip to Hongyun Huaning (Hangzhou) biomedical Co., Ltd., only 1km away from Alibaba Binjiang Park, on an afternoon in May, to explore the people and things behind the development of GPCR antibody drugs, which has been focused on "ten years as one day" Dr Jing Shuqian has been engaged in new drug discovery and drug development in Anjin for more than 14 years Ten years ago, he left the then world's largest biotechnology company to start his own business in China After many twists and turns, Jing Shuqian met partners willing to help him realize his vision in 2010, and established Hongyun Huaning in Hangzhou, which means "Hongyun helps the world, Huaxia Kangning" At that time, Dr Jing Shuqian, founder of Hongyun Huaning, although the U.S financial crisis was not long ago, the momentum of biopharmaceuticals did not diminish Since 1997, the first personal antibody drugs (Note: Rituximab) appeared, more than 30 antibody drugs have been listed in 2008 Scientists have shifted their attention from peptide drugs such as insulin to monoclonal antibodies Jingshuqian also wants to make a breakthrough in the development of antibody drugs, but he is unwilling to follow the hot spot at that time or just follow the steps of large pharmaceutical companies In 2008, he saw an opportunity from a number of monoclonal antibodies already on the market Jingshuqian found that most of the antibody drugs on the market are targeted at EGFR, HER2, VEGFR and other cell membrane surfaces Although the GPCR family protein target has a high drug production rate, it is all small molecule or polypeptide drugs This is because of the complexity of GPCR protein structure To obtain the antibody drugs for this target is still a worldwide problem that has not been solved at that time Therefore, FDA has not approved any GPCR antibody drugs to go on the market before Jing Shuqian vaguely felt that this was a historical opportunity to fill the gap He first thought of Zhang Cheng, a student at the University of California, San Diego (UCSD), who had more than 10 years of experience in drug development of GPCR In the summer of 2010, Jing Shuqian asked Dr Zhang Cheng out to chat, said his idea of going back to China to start a business, and invited him to join in At that time, Zhang Cheng didn't know much about the entrepreneurial atmosphere in China and hesitated a little Until a year later, when Hongyun Huaning's laboratory in Hangzhou had been completed, the basic instruments and equipment were in place Jing Shuqian once again sent out an invitation to Zhang Cheng This time, after careful consideration, Zhang Cheng readily agreed Recalling the scene of that year, Zhang Cheng still remembers it to this day "The urging of senior brother Jing Shuqian and the infection of domestic entrepreneurial atmosphere made me determined to return to China, and I hope to have the opportunity to make new drugs to treat major diseases." At the end of 2011, Zhang Cheng persuaded his family to go all the way to Hangzhou and join Jing Shuqian's entrepreneurial team Unlike Zhang Cheng, Guo Yong, who described himself as "woodlouse", moved his family from Chengdu to Hangzhou Guo Yong once worked in Huashen group and Kanghong Pharmaceutical Co., Ltd in the R & D and management of innovative drugs The well-known "conbercept ophthalmic injection" is a project in Kanghong Pharmaceutical Co., Ltd as a core R & D personnel, he has participated in nearly 10 years At present, he is the vice president of the company, responsible for the registration of products at home and abroad, clinical trials and product development project management "I also accidentally learned that the antibody drugs developed by Hongyun Huaning started to innovate from the target, and at that time, most of the domestic enterprises engaged in the development of biological drugs were doing me better innovation." Guo Yong told reporters, "there are only a few antibody drug R & D companies with the source innovation ability in China Inspired by Dr Jing, they feel that their accumulated experience in new drug R & D complements the existing team and can contribute to the development of Hongyun Huaning So I discussed with my family and moved to Hangzhou to join the team " Dr Fan Kesuo, vice president of pharmacy of Hongyun Huaning, was attracted by the company's R & D strategy at an academic seminar in 2015 and joined the company in August of that year Fankesuo has worked in famous pharmaceutical enterprises and institutions such as jianzan, Roche, waters, BMS and National Institutes of health for more than 15 years before After returning to China, he has been engaged in the research and development of double anti drugs in youzhiyou, and is familiar with the quality analysis, process development and clinical application of biological drugs At present, Hongyun Huaning is mainly responsible for screening more highly expressed cell lines and CMC Hongyun Huaning core R & D team (from left: Guo Yong, fan Kesuo, Jing Shuqian, Zhang Cheng) reporter learned that Hongyun Huaning has 75 employees, nearly 30 doctors and returnees But jingshuqian said that the talent gradient construction is far from what he expected In addition to adding suitable talents to the drug development pipeline, the enterprise governance is also relatively open At the beginning of May, Mr Zhu Bing, who once served as CFO and COO of Sino US Guanke, also joined Hongyun Huaning "Making innovative medicine is like opening a new restaurant, target development is like selecting ingredients, and drug development is like shaping cooking skills Good chefs must be familiar with good ingredients, but everyone has limited energy Even good chefs may not be proficient in restaurant management, service elements and food packaging Pharmacy is a systematic project Different talents need to join in the whole chain at different times "Jing Shuqian made a simple analogy It is not difficult to find out from the list of executives of Hongyun Huaning that the members of this team have distinct age levels, highly complementary industrialization experience, and mutual integration of local and foreign cultural backgrounds, forming a stable and efficient operation system In addition, jingshuqian and Zhangcheng both mentioned that the accumulated thinking mode and international vision in Amgen are of great benefit to the R & D management of Hongyun Huaning For example, during the work in Amgen, the R & D team had a habit of having a happy hour every five days Everyone gathered together to brainstorm, and made a mind map of the discussion results, which eventually became the prototype of some experimental technology roadmap Now, they bring this work habit and atmosphere to fortune Huaning During 2011-2015, the total sales revenue of drugs developed based on GPCR family protein target was close to $900 billion The typical heavy bomb drugs include valsartan (AT1R), fengomod (s1pr) and GLP-1R Jingshuqian has been targeting the GPCR family protein with mature mechanism and high drug yield since he started his business As the chief scientist, Zhang Cheng's main task is to find out the GPCR family protein target suitable for preparing monoclonal antibodies People who are familiar with GPCR family proteins all know that GPCR has seven transmembrane regions, which is difficult to carry out structural biological analysis, and its natural expression rate is very low It is very difficult to obtain soluble GPCR antigen with biological activity, and antigen is the necessary substance to stimulate animals to obtain immunity and produce antibodies Therefore, the early antibody screening process is very difficult Like most start-ups, Hongyun Huaning's first few years are hard and lonely In the early days of his career, even on weekends or evenings, Zhang Cheng went with his senior From time to time, the experimental scheme was discussed, and from time to time, the viewpoint of literature was shared During the day, I put on my white coat and shuttle between the shaking bottle and the mouse lab It took them almost three years to overcome the worldwide problems of GPCR antigen preparation and functional antibody screening, and set up a technical platform for efficient screening and preparation of GPCR antibody candidates Jingshuqian and Zhang Cheng combined their years of drug research and development experience Among more than 370 GPCR drug targets, GLP-1R and ETA, two targets with both the prospect of drug and market, were selected as the initial development direction, and candidate antibody molecules were successfully obtained GLP-1R has produced several blockbuster drugs, such as lilalutide, dulaglutide and somalutide However, no GLP-1R antibody drug has been listed before, and Hongyun Huaning's antibody drug for endothelin receptor is the world's first After the target was determined, and after more than two years of process improvement and optimization, Hongyun Huaning screened the cell lines that could produce 2-3g / L expression During this period, Guo Yong and fan Kesuo successively joined in the research work of pharmacy, pharmacodynamics, pharmacokinetics and toxicology of candidate molecules developed by Hongyun Huaning based on these two targets, which prepared sufficient preliminary data for the application and development of clinical trials "I spend one-third of my time every day on project schedule control," Guo Yong told reporters "No way, new drug development is like this When patients are racing against time, drug companies are racing I have to keep a close eye on it Quality assurance, schedule assurance and cost control are the focus of my work " Guo Yong has been preparing the application for clinical trials since he joined Hongyun Huaning in February 2015 At that time, it took an average of 18 months from cell line construction to completion of preclinical research and preparation of clinical application data to submission of CDE, plus the time for domestic review and approval, which generally took at least 2 years to enter human clinical trials In April 2016, the first clinical trial of Hongyun Huaning gma102 was conducted in Australia