Bio-innovative drug segmentation market strategic investment prospect
——— monoclonal antibody drugs articles
[Author: Zhou Yong, founder/Chairman of Gaosheng Biomedicine, co-founder of Gaochuanghui Biomedical Transformation Platform, Vice President of Beijing Haidian District Biological and Health Industry Association, Vice President of Chongqing Pharmaceutical Industry Association, Chongqing City innovation and entrepreneurial leading talents;
The biomedical industry is composed of the biotechnology industry and the pharmaceutical industry. Bio-innovative drugs are emerging industries in the pharmaceutical industry. The national “Twelfth Five-Year Plan†has identified the focus of biomedical development, including monoclonal antibody cloning drugs, protein drugs, genes and nucleic acid drugs, etc. Excellent policies will actively promote biomedicine in China. With rapid development, the biomedical industry is expected. Among them, monoclonal antibody drugs, as a biologically targeted drug with unique advantages, have the characteristics of high specificity, strong targeting and low toxic and side effects, and have significant effects in treatment. With the continuous development of antibody technology and the emergence of new antibodies, monoclonal antibody drugs have become one of the fastest growing areas in the pharmaceutical industry. One-quarter of the biotech drugs currently under study are monoclonal antibody drugs. Various monoclonal antibody derivatives have emerged during this period, including antibody drug conjugates, small molecule antibodies, and bispecific antibodies. The domestic monoclonal antibody field faces the dual opportunities of rapid market growth and import substitution. Monoclonal antibody research has been included in the 863 Program and national key research projects. The research, development and market application of monoclonal antibody drugs will certainly attract the participation and layout of a large number of pharmaceutical companies. With this shareholder wind, there will be autonomous monoclonal antibodies in the future. Class dominance should not be just a dream
I. Definition and classification of monoclonal antibodies
A highly homologous antibody produced by a single B cell clone, directed only to a particular epitope, is referred to as a monoclonal antibody. Traditionally, hybridoma technology has been used. Hybridoma antibody technology is based on cell fusion technology, and sensitized B cells with the ability to secrete specific antibodies and myeloma cells with unlimited reproduction ability are fused into B cell hybridomas. By culturing a cell population with a single hybridoma cell having such characteristics, a characteristic antibody against an epitope can be prepared, that is, a monoclonal antibody.
Through genetic engineering, the antibody molecules in the monoclonal antibody and the human body have as similar characteristics as possible, and the antibody is humanized. From the murine source to the whole source, the probability of human anti-mouse immune response in the patient is gradually reduced, and the therapeutic effect and safety are gradually improved. Therefore, the whole human monoclonal antibody is the trend of development of monoclonal antibody (Table 1). However, as the degree of humanization increases, the affinity of monoclonal antibody products will gradually decline. Therefore, improving the affinity of monoclonal antibody products under the premise of eliminating human anti-mouse response is the core technical barrier for the development of monoclonal antibody drugs.
Second, monoclonal antibody drug development process and trends
In general, a monoclonal antibody drug company needs an upstream R&D platform to screen out the ideal monoclonal antibody; and it has a high-efficiency and large-scale fermentation to express the monoclonal antibody; it also needs to be able to separate and purify the monoclonal antibody with high efficiency and high purity. Such a company has the core competitiveness of the development and production of monoclonal antibodies.
1. Phage display technology has become the mainstream of human monoclonal antibody screening. With the deepening of the humanization process of monoclonal antibodies, phage display technology (using PCR technology to amplify the entire set of antibody heavy chain variable region (VH) and light chain variable region (VL) genes from human immune cells, Large-scale monoclonal antibody screening platforms that are cloned into phage vectors and expressed in the form of fusion proteins on the surface of their outer shells are gaining increasing attention. The technology can not only obtain the whole human monoclonal antibody, but also does not require cell fusion, the test period is short, and the process is simple. It is a major breakthrough in the preparation technology of human antibody. At present, the mainstream domestic monoclonal antibody manufacturers use phage display technology to screen the monoclonal antibody.
2. Expression culture technology is the key to yield formation and quality control of monoclonal antibody. Expression method, reactor size, expression system and expression level are important indicators for judging the technical level of enterprises.
Table 2 Three elements of expression culture technology
3. Separation and purification technology is the last key link in the production of monoclonal antibodies. The industry generally uses ammonium sulfate precipitation, ion exchange chromatography, and protein-Sepharose affinity chromatography to purify the monoclonal antibody. The rate will be reduced by 13%, so ensuring the purity while maximizing the yield is also an important part of testing the production level of the company.
Figure 1 Industrial production purification process of monoclonal antibody
Third, the development and production characteristics of monoclonal antibody
The development of monoclonal antibody drugs is characterized by high investment, high price and high profit. The development cycle of monoclonal antibodies lasts for 10-15 years, but once it is successfully listed, it can bring rich returns to manufacturers. Large-scale antibody production costs about $200/g, and the price is as high as $5,000/g, and the production cost is only 1/25 of the selling price. By 2016, there will be about $25 billion in patents for monoclonal drugs worldwide, and the era of antibody drug imitation is coming.
Fourth, monoclonal antibody drug development and production trends
The proportion of human monoclonal antibody is increasing, and the target of monoclonal antibody is gradually diversified. In addition to the traditional cell surface antigen, it also includes common cytokines. Some monoclonal antibodies can even recognize multiple epitopes. And the structure of the monoclonal antibody is not limited to the intact monoclonal antibody molecule. The treatment options for joint small molecules and so on have gradually increased, and are increasingly valued by medical workers. Therefore, as a high-tech drug, the technological level of the monoclonal antibody drug company determines its competitiveness, and also determines the therapeutic effect and market value of the drug.
Mouse-to-humanized antibody: reduces antibody immunogenicity
Antibody-small molecule drug conjugates (ADCs): targeted antibody drugs, a class of antibodies that are conjugated to anticancer agents
Bispecific antibody (BsAb): genetically engineered two antibody fragments targeting different antigens together, with two antigen binding sites, can play a synergistic effect, thereby improving the therapeutic effect
V. Development of the global monoclonal antibody industry
In 1997, the FDA approved Genetech's chimeric antibody, Rituxan, which was extremely successful. As the first chimeric antibody to treat tumors, Rituxan became the first star drug in the field of monoclonal antibodies. The $10 sales club was followed by the chimeric antibody Remicade (infliximab) and human monoclonal antibody Herceptin (trastuzumab) and Synagis (palivizumab). The industry has expanded rapidly, with sales ranging from $310 million in 1997 to $91.63 billion in 2015 (Figure 2).
Currently, there are 55 monoclonal antibodies approved by the US FDA, including 49 monoclonal antibodies and 6 antibody-functional Fc fusion proteins (Table 3). By the end of 2013, there were nearly 350 monoclonal antibodies in clinical trials, covering tumors, autoimmune diseases, anti-infections, respiratory diseases, etc. Among them, the market with the largest number of tumors and autoimmune diseases, accounting for the total sales of monoclonal antibodies. 50% (Table 2). At present, monoclonal antibody has become a large category of biopharmaceuticals, and since there are only 50 kinds of monoclonal antibodies approved for marketing, the monoclonal antibody has become a heavy bomb concentration camp. In 2015, adalimumab was The US$14.12 billion in sales ranked first in the global drug rankings, and there were 6 blockbuster products with global sales of US$5 billion to US$10 billion in 2015 (Table 3).
Figure 1: Global approved monoclonal antibody-treatment category (according to 2015 sales statistics, currency unit: US dollar)
FDA-approved monoclonal antibody/fusion protein drug star product
Through the process of single-line industry products and company development, we found that in the early stage of rapid development of the monoclonal antibody industry, large-scale comprehensive pharmaceutical enterprises have no monopolistic advantage in terms of technical reserves and R&D personnel. Small and medium-sized enterprises with excellent texture can pass single or several The fist products grew rapidly and maintained their advantages over the years. However, with the growing scale of the monoclonal antibody industry, especially the emergence of blockbusters, large-scale integrated pharmaceutical companies have acquired the leading position in the industry by acquiring the small and medium-sized pharmaceutical companies with strong R&D capabilities and star drugs. More and more obvious (Table 3). With Roche's acquisition of a 44% stake in Genetech for US$46.8 billion, it marks the transfer of almost all the blockbuster drug ownership in the market to large pharmaceutical companies. The international monoclonal antibody market will form a unique Roche, Johnson & Johnson, AstraZeneca, Pfizer and other large pharmaceutical companies. Keeping up with the new pattern, the industry has entered a mature period. More than 20 new monoclonal antibody drugs may still be available before 2017, supporting the overall expansion of the monoclonal antibody market. The market for monoclonal antibodies began to enter a period of rapid growth after the listing of Rituxan. In 2008, it grew 23 times compared with 1999, with an average annual growth rate of 42%. After 2004, the market for monoclonal antibodies gradually declined to around 20%. Since 2010, the average annual growth rate of the global monoclonal antibody market is expected to be 9.3%, and the growth rate has returned to normal.
6. Development of China's monoclonal antibody industry
1. Development status of China's monoclonal antibody market
Compared with the tens of billions of dollars in the international market, the size of the domestic monoclonal antibody market is still far less than that of developed countries. As of March 2016, the State Food and Drug Administration approved a total of 22 antibody drugs (12 imports, 10 independent research and development or joint research and development), mainly related to anti-tumor, anti-rejection, autoimmune diseases and other fields (Table 6) . Among the imported products, the sales of rituximab and Herceptin are the largest, but most of the monoclonal antibodies are still in the introduction period, far from the situation of blockbuster. There are many reasons for the narrow market in the domestic monoclonal market, including medication habits, price factors and inadequate medical insurance.
2. Prospects for the development of China's monoclonal antibody market
Although the short-term domestic market share of domestic monoclonal antibodies is limited, the growth rate and sustainability and potential market size have huge investment value in the domestic monoclonal antibody market. In 2014, the domestic market for monoclonal antibody drugs was only 5 billion yuan, mainly concentrated in the field of cancer. For example, the earlier listed companies such as rituximab and Herceptin, the compound growth rate of the two from 2003 to 2012 was as high as 46% and 74%, much higher than the overall compound growth rate of 23% in the pharmaceutical industry during the same period, with sales reaching 535 million. Yuan and 387 million yuan, it can be seen that explosive growth is beginning to take shape. According to China's industrial policy, population structure, ability to pay, willingness to pay, medication habits and other considerations, the rapid growth of the domestic monoclonal antibody industry will continue in the next few years.
Figure 2 Chart of domestic monoclonal market size in 2009-2014
Source: National Bureau of Statistics
China's monoclonal antibody development trilogy
3. The development direction of domestic monoclonal antibody enterprises
Because China's monoclonal antibody companies' drug research and development accumulation, R&D investment, scientific and technical personnel and team management are not far from the international first-line monoclonal antibody companies of Genentech type, I think the possibility of domestic enterprises catching up with foreign competitors through original monoclonal antibodies is very high. low. Therefore, the “Me-too†strategy has become a practical strategy for domestic monoclonal antibody companies to expand locally. "Me-too" drugs use the mechanism of action and structure-activity relationship of known drugs to circumvent the patent rights of existing drugs, and obtain new patented drugs with equivalent efficacy through structural modification or structural modification. Monoclonal antibodies have large molecular weights and complex structures, while relatively important core structural sites are relatively few. With the expiration of some foreign monoclonal antibody patents, a large number of imitations of monoclonal antibodies will be available soon (Table 5). Compared with foreign countries, China's compound structure patents can claim a small scope of rights. Enterprises can retain the main therapeutic sites to circumvent patents by modifying the antibody structure during drug design, and can also choose different expression systems and expression conditions. Avoid process patents. Due to the huge gap in upstream research capabilities, domestic monoclonal drug companies have a small gap with domestic development in the development and production of “Me-too†drugs. Some enterprises have mastered a full set of middle and downstream technologies from antibody humanization, antibody screening technology to antibody expression and purification. The main fermenter of first-line pharmaceutical enterprises has reached the level of 1,000 L, and the expression level has reached 10 g/L. This allows the equivalent monoclonal antibody to be put into production as soon as it is successfully developed, and it can quickly pay off. All in all, the growth rate of monoclonal antibody in China is rapid, and it is already in the early stage of explosive growth (Table 7). The development of “Me-too†drugs will become a breakthrough for the rapid development of domestic monoclonal antibody companies, and the pioneers will benefit more.
This article was originally created by Zhou Yong, the founder of Gao Sheng Pharmaceutical. Welcome to reprint and forward, but must indicate the source.
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