Antibody drug development capability test of local enterprises: Where is the main bottleneck? How competitive is it?

In the global scope, with the rapid development of biotechnology, the development direction of the pharmaceutical industry has gradually changed from chemical small molecule drugs to biological drugs First of all, we need to clarify the relevant concepts of biological products and preparations According to the FDA definition of biological products, biological products are mainly divided into four categories: blood products, vaccines, proteins and cell / gene therapy products Among them, many blood products and vaccines have been sold in the domestic market, and the development of these products can be traced back to the 1960s, but most of these products, especially vaccines, are products under the planned economy, and most of the manufacturers are concentrated in state-owned enterprises and some scientific research institutions As the market is not fully competitive, the power for quality requirements and process optimization is not strong This is why most of our blood products still adopt the traditional low-temperature ethanol method and the column chromatography of some process sections, while the international advanced full process column chromatography technology has not been adopted in China The same is true of vaccines Recombinant protein and antibody drugs are new life science and technology in recent 20 years Foreign antibody drugs first appeared on the market in 1992, and the whole business process is only 20 years The development of biotechnology in China depends on the cultivation of a large number of biotechnology talents in the early 21st century, the support of national policies and the influx of a large number of funds This article will explain the current situation of the development of antibody drugs in China and the existing problems The domestic listing of imported drugs dominates the world Only a few domestic pharmaceutical enterprises can commercialize the production of 63 antibody drugs, including 57 monoclonal antibodies and 6 receptor Fc fusion proteins with antibody function, which have been approved globally as of June 2017 According to Xianda data v3.2, a total of 10 monoclonal antibodies have been approved for import in China The average time difference between the first global market and the domestic market of these monoclonal antibody products is 5 years Among them, cetuximab has the shortest time difference in the international and domestic market, only one year; the longest time difference is etanercept, the time difference between the foreign market and the domestic market is 12 years In addition, the number of manufacturers applying for these monoclonal antibody products is much less than that of chemical drugs No matter in clinical or production application, it is under 5 manufacturers, which fully shows that the commercial production of McAb is still concentrated in the hands of a few players Compared with domestic monoclonal antibodies, there are only three manufacturers in China that can carry out commercial production of monoclonal antibody products, namely: yisaipu of China CITIC Guojian, nitzumab of Baitai Pharmaceutical Co., Ltd., which was listed in 2006, and conbercept of Sichuan Kanghong Pharmaceutical Co., Ltd., which was listed in 2013 CFDA also approved Shanghai SAIJIN bio's qiangke and Haizheng pharmaceutical's ambano in recent years Both of these products, like ISEP, are enri's biological analogues As yisaipu was listed in 2006 and its price is relatively low, according to IMS data, the current sales scale in the market is about 6-8 times of the original yannli The sales revenue of nitzumab in 2014 was about 120 million yuan In the first year of 2014, CommScope's sales revenue was about 25 million yuan A large number of other biological analogues and new monoclonal antibodies are still in the process of application or clinical research and development The R & D transformation of domestic mainstream R & D enterprises is the main development direction of biopharmaceutics According to the data of Xianda data v3.2, there are 103 domestic enterprises involved in the R & D and application of McAbs Among them, Qilu pharmaceutical has the largest number of monoclonal antibodies to be declared, with 9 projects to be declared; followed by Shanghai Fuhong Hanlin and Jiahe biology See Table 2 for details According to the existing manufacturers applying for McAb drugs, we can see that the manufacturers pouring into this field are mainly divided into these categories: first, comprehensive pharmaceutical enterprises with strong R & D strength, represented by Qilu pharmaceutical, Zhengda Tianqing pharmaceutical and Haizheng pharmaceutical The original pillar products of Qilu pharmaceutical industry are monosialotetrahexosylganglioside sodium for injection (Shenjie) and small molecule tumor drugs Now the large-scale application of monoclonal antibody products can be used as an extension of the original tumor products Zhengda Tianqing is the leader of the generic pharmaceutical enterprises, so it is also a matter of course to copy biological products Haizheng pharmaceutical industry lags behind Hengrui in the era of chemical medicine, but its production strength cannot be underestimated It has entered into recombinant protein products and monoclonal antibody products in an all-round way, hoping to pull back a round in biological preparations Second, companies with biotechnology research background, represented by Fuhong Hanlin, Jiahe biology, Xinda biology, etc Most of the founders of such enterprises have a certain technical background, and most of the core members of the team also work in large-scale Biopharmaceutical Enterprises, and have some experience in biopharmaceutical development and commercial production Third, research institutes of colleges and universities, mainly for the application of research projects of some scientific research institutions As academia and industry become more and more closely connected, these projects may later be transferred to some enterprises that expect transformation, have sufficient funds and lack of technology The implementation of bottleneck production and cost competition in the development of biological similar drugs are different from that of chemical drugs, and the production threshold of biological products is higher From cell culture, construction of plasmids, expression of products, downstream purification to quality control and other links, high technical content is needed Therefore, in many occasions, it has been mentioned that the bottleneck of the commercialized production of biological drugs, in addition to the early research and development, the development of production technology should be the most concerned place for domestic enterprises aiming at the antibody market in the future Different from chemical drugs, biopharmaceutical products can not be accurately linearly amplified The acquisition of products depends on the exploration, debugging and long-term experience of various production links Therefore, if there is no guarantee of relevant stable technology for a large number of domestic antibody projects, the road to commercial implementation in the future is still quite difficult Because antibody drugs are aimed at relatively single indications, it is necessary to know the accurate market demand in the production, rather than to carry out more random development according to the scale of the built production line For example, the scale of production workshop depends not only on the size of fermentation tank, but also on the improvement of unit expression Because a large number of antibody projects developed in China are imitation products, the only way for these projects to survive in the future is to reduce the production cost per unit This requires us to pay more attention to the development of production process and improve the expression efficiency of cells in the process of antibody development As we all know, the production of antibody drugs needs a lot of financial support Not long ago, Baiji Shenzhou joined hands with Guangzhou Development Zone to invest 2.2 billion yuan to establish antibody production base, while Yaoming biology also invested 150 million dollars to build production plant Based on such a high cost of plant construction, various innovative small and medium-sized biotechnology companies may finally choose OEM to complete the commercial implementation of the project The MAH system issued in 2015 ensures the feasibility of the implementation of this path Conclusion: the development of antibody drugs in China is mainly based on the development of biological similar drugs However, due to the characteristics of biopharmaceuticals, the development of biopharmaceuticals is more challenging than that of chemical ones The biggest challenge lies in the technicality of production process When making the project development plan, domestic manufacturers need to consider and design the development and selection of production process, GMP management and other production related matters earlier than chemical production, so as to carry out more commercial activities in the follow-up monoclonal antibody market and compete with the original products.