New antibody drugs: the future power of China's biopharmaceutical industry -- value, territory and development strategy (double antibody)

The antibody drugs that have been put on the market involve tumor, immune related diseases, in addition, there are many fields such as nerve, respiratory, metabolism, bone diseases and so on, which provide a wealth of products and strategies for the treatment of human diseases and show great social benefits In 2016, the sales volume of antibody drugs in the world has exceeded 100 billion US dollars (including Fc fusion protein), which has achieved great success in clinical and commercial fields At present, people have developed some new directions through the transformation of antibody drug structure, such as antibody conjugates, bispecific antibodies, single domain antibodies (also known as nano antibodies) and other new antibodies This adjustment helps to improve some inherent defects of standard structure antibodies and better meet the clinical drug demand New antibody drugs represent the new development direction of antibody industry and are the future power of China's biological medicine industry In this paper, the general situation of bispecific antibody drugs was reviewed 1 Basic information of bispecific antibody (1) bispecific antibody (BsAb) is a kind of antibody molecule which is constructed by antibody engineering and gene engineering technology and can combine two antigens or two epitopes at the same time There are three main production methods: recombinant DNA method, cell hybridoma technology and chemical coupling method Among them, recombinant DNA is the most commonly used method At present, there are three bispecific antibody drugs approved for marketing in the world, namely catumaxomab, blinatumomab and emisizumab Table 1 is as follows: Table 1 the bispecific antibody drugs approved for marketing at present (2) the bispecific antibody drugs are generally divided into two categories according to their structures: IgG structure and non IgG structure The IgG structure can be divided into symmetric and asymmetric structure The structure is as shown in Figure 1: the multi structure design of the bispecific antibody in Figure 1 (3) the antibody technology platform is different from the antibody molecules in the general sense The bispecific antibody does not exist in the natural state, and needs to be manually prepared by recombinant DNA or cell fusion technology After years of technical research, there are many different structural design strategies The representative bispecific antibody technology platforms are listed in Table 2: Table 2 list of bispecific antibody technology platforms 2 The application value of bispecific antibody The application value of bispecific antibody is various At present, it is mainly concerned about its application in disease treatment At the same time, bispecific antibody has been used in clinical diagnosis , medical imaging and other aspects show great potential and important value (1) At the same time, blocking two pathological pathways and some complex diseases are caused by many reasons Multiple signal pathways are involved in the development of Pathology, and single target therapy is often limited Bispecific antibody can block the two pathological pathways at the same time, realize the disease treatment effect that many monoclonal antibody drugs or combination drugs can't have at the same time, play a special biological function, and have a broad prospect In addition, some bispecific antibodies can penetrate the blood-brain barrier and target the pathogenetic mediators of nervous diseases (2) The application of car-t in tumor immunotherapy with T lymphocytes as the main effector cells, such as chimeric antigen receptor T cells (CART), is a major breakthrough in the field of immunotherapy Bispecific antibodies can redirect T cells and natural killer cells to tumor cells For example, the bispecific antibody constructed by combination of anti-CD3 antibody and tumor targeting antibody can recruit T cells to approach tumor cells, produce guiding effect and mediate T cell killing In addition, compared with car-t, bispecific antibody drugs have the advantages of controllable dosage and flexible drug cycle, so the application in the field of tumor immunotherapy has also attracted more and more attention (3) The detection and diagnosis application of bispecific antibody can be designed as a specific antigen and a detection related part, which can be used as a cross-linking agent Immunoassay based on bispecific antibody has been applied to the detection of tuberculosis, hepatitis B and atypical pneumonia Due to its fast, simple and highly sensitive characteristics, bispecific antibodies are being used to develop various types of tumor detection It is also used in immunohistochemistry and radioimmunoassay, as shown in Figure 2 Compared with the single specific antibody, the double specific antibody can simplify the diagnostic test process and reduce the false-positive reaction Figure 2 immunoassay based on bispecific antibody (4) transport vehicle bispecific antibody can also be used as a transport vehicle to deliver drugs, radioisotope labeling, nanoparticles, etc., and enrich drugs at tumor sites, which is a new carrier tool 3 The key of the development layout of domestic and foreign enterprises in the development and preparation of dual reactance is to have its own structure and preparation technology platform There is a saying in the industry that "McAb specific target, double antibody specific platform" In recent years, multinational pharmaceutical enterprises such as Roche, Johnson & Johnson, Amgen, Pfizer, Servier and Takeda have invested heavily in the development and layout of bispecific antibodies Taking Roche as an example, more than 30% of the research and development pipelines of macromolecular drugs are located in bispecific antibodies Not only that, on the basis of internal development of its own formats and expansion of R & D pipeline, Roche also actively introduces other different formats through technology to strengthen technical reserves Foreign pharmaceutical giants have laid out double anti DDoS, so what are the domestic leading enterprises of double anti DDoS? Incomplete statistics show that at present, there are more than ten enterprises in China, such as youzhiyou biopharmaceutical, tress, Fosun Pharmaceutical, Xiansheng pharmaceutical, Tianjing biological, Corning Jerry, bosengji pharmaceutical, Anmai biological, jiannenglong pharmaceutical, Tianyan pharmaceutical, Junshi biological, Xinda biological, Kangzhong biological, Lizhu, Hengrui, which are rich in developing countries International cooperation, the introduction of technology platforms, and strategic complementarity, but the products are still in the early stage Figure 3 layout of bispecific antibody in domestic pharmaceutical enterprises 4 Development difficulties and key points of bispecific antibody drugs , medical imaging and other fields have greatly expanded the application scope and space of monoclonal antibodies, which is an important development direction of monoclonal antibodies in the future and one of the future forces of China's biopharmaceutical industry However, it is precisely because of this structural transformation that some of the characteristics of the natural antibody itself have been changed, so it has brought new challenges in the aspects of pharmacokinetic properties, process development, industrial production, etc So what are the difficulties in the development of double reactance? (1) Although the market prospect of structural design is clear, the application-based antibody structural design is undoubtedly one of the difficulties in the development of double antibodies This requires that at the beginning of development, attention should be paid to how to balance and coordinate the safety and effectiveness of the two targets, dosage and cycle, affinity with different epitopes, etc patent issues also need to be considered in advance Specific structural adjustment still needs strict clinical investigation, accumulation and verification (2) At present, the development of technology platform has its own characteristics There are dozens of technology platforms, but there is still a lot of room for improvement We need to constantly explore and optimize them to develop platform technology with properties, production process feasibility and scalability In addition, we should also consider the universality of production platform It is also one of the measures to be considered to introduce the double resistance technology platform with different characteristics from abroad (3) The structure of preparation and industrialization of bispecific antibody is special, and it is difficult to realize the structural characteristics based on the function Because of the structural adjustment, the molecular stability, immunogenicity and pharmacokinetic properties are changed, and the molecular preparation and industrialization are much more difficult than the monoclonal antibody This is what needs to be considered at the beginning of development 5 outlook In recent years, China has attached great importance to the development of antibody drug industry, actively invested in research and development funds, intensively issued supporting policies, and guided the rapid development of the industry However, we should clearly see that the international competitiveness of domestic biological drug industry is still weak, the innovation ability is not strong, the core technology is less, the research and development target is single and highly repetitive, and the bioreactor, purification system and The problem that process equipment, raw materials, reagents and culture media are largely dependent on imports is very obvious, which greatly increases the cost of large-scale production of antibody industry in China In the absence of domestic antibody products, almost all of the antibodies used in clinical use are imported from abroad, which reduces the living space of domestic antibody drugs The rapid development of new antibody drugs in China needs close cooperation and division of labor in the whole industrial chain What are the latest bright technologies and new ideas in the research and development of bispecific antibody drugs? What are the latest developments and trends at home and abroad? Our meeting will give you answers Biological Valley The Forum on new antibody drugs will be held in Shanghai from October 26 to 27, 2018 Focusing on the discovery and design of new antibody drugs, the selection of development strategies, and the transformation of new technologies and achievements, the forum invites top experts in the research and development and production of new antibody drugs at home and abroad to share industry experience, demonstrate technological breakthroughs, and present the latest progress of new antibody research and development and industrialization Exhibition The conference will build a platform for experts and industry leaders to exchange, share and cooperate, and jointly promote the healthy and rapid development of China's antibody drug industry! 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