Don't just focus on PD-1 / L1, these directions of tumor immunotherapy may also become the hot money

Tumor immunotherapy seems to be a word with its own halo The top ten scientific breakthroughs in 2013 science journal, Nobel Prize background, multiple capital endorsements, subversion of traditional tumor treatment methods, etc are just the tip of the iceberg of its infinite possibilities From the discovery of multiple immunosuppressive points, the promotion of a large number of clinical trials, the listing of the first PD-1 / L1 inhibitor in the world, to today's multi-faceted flowering of immunosuppressive drugs, cell therapy, tumor vaccine, double antibody / multi antibody therapy, etc., tumor immunotherapy has been hot, and has been widely concerned by researchers, capital markets and pharmaceutical companies all over the world In recent years, PD-1 / L1 inhibitors have caused a great wave of heat without any accident in the domestic market It is mainly based on the discussion of whether they are included in the medical insurance The proponents and the opponents have different opinions, and the competition is quite intense However, considering that the 2019 medical insurance catalog will be published soon, the editor will not elaborate too much here, and we will wait for the result Today's article is mainly to use PD-1 / L1 inhibitor as an introduction to discuss the current situation of tumor immunotherapy in China If there is any deficiency, please point out Overview of tumor immunotherapy in recent years, the domestic innovative enterprises of tumor immunotherapy research and development have grown rapidly, among which three PD-1 have been approved for listing (Junshi biology, Xinda biology, Hengrui medicine), in addition, PD-L1 and CD47 have multiple pharmaceutical enterprises layout, while LAG-3, Tim-3, tigit are relatively few The hottest targets of antibody drugs in immunoassay sites include OX40 and 4-1BB Compared with inhibitor antibodies, they have technical difficulties and characteristics, and there are relatively few enterprises According to incomplete statistics, in 2017, there were 138 enterprises applying for or having clinical trials of tumor immunotherapy, showing an increasing trend year by year The R & D enterprises are mainly concentrated in Shanghai, Jiangsu, Beijing, Guangdong and other regions There are 33 companies in Jiangsu, represented by bosengji, Xinda biology, kangningjierui, tricellular group, etc.; 30 companies in Shanghai, represented by Junshi biology, sibyman, Fuhong Hansen, etc.; 21 companies in Beijing, represented by Baiji Shenzhou, Baitai biology, Yiming cell, etc.; 12 companies in Guangdong, represented by Yuanzheng cell, heyikang biology, etc In addition, some traditional Chinese medicine, chemical medicine and even medical equipment enterprises, through independent R & D or M & a cooperation, rapidly establish the R & D pipeline of biological drugs, especially tumor immunity, such as Lepu, Tianshili, LVYE pharmaceutical, Changbu pharmaceutical, Yuheng pharmaceutical, Zhixiang pharmaceutical, etc The hottest target is PD-1 / L1 PD-1 / L1 inhibitor, which is one of the largest varieties in the field of tumor innovative drugs In 2018, the global market exceeded US $15 billion, keytruda and opdivo ranked among the top ten best-selling drugs in 2018 with us $7.171 billion and US $6.735 billion respectively Such a large piece of cake, the Chinese market is bound to become the indisputable place for major pharmaceutical enterprises In the past 2018, many people think it is the first year of PD-1 drugs in China In this year, two foreign-funded products (BMS: opdivo, MSD: keytruda) and two domestic funded products (Junshi biology: trepril mAb and Cinda biology: cindili mAb) were approved for listing Subsequently, in May 2019, the third domestic PD-1 drug (Hengrui medicine: carrizumab) was approved for marketing, which has formed a 2 + 3 PD-1 / L1 competition pattern in China At present, there are 37 PD-1 / L1 R & D companies in different approval stages of nmpa, and it is expected to reach 15 listed products in 2020 Among them, Baiji Shenzhou (tirelizumab) and AstraZeneca have submitted the listing application of PD-1, which is expected to be approved in the second half of 2019 and 2020; there are 7 in phase III clinical stage, including kangfang biology, Fuhong Hanlin, Corning Jerry, cornerstone pharmaceutical, sidilu, Zhengda Tianqing, etc; There are 8 enterprises in phase II clinical trials, including Harbin Yuheng, Jiahe biology, Kelun group, etc.; 8 enterprises in phase I clinical trials, including Shijiazhuang Pharmaceutical Group, lizumab, cornerstone pharmaceutical, Zhaoke pharmaceutical, etc.; in addition, there are 6 enterprises in clinical trials, including 4 from local companies In the past few years, for many start-ups, there was a joking situation: "one of the most important points of capital investment is whether you have a PD-1 / L1 layout" It seems that this is a standard configuration in the field of cancer drug innovation in China, but the reality is very cruel The market is huge and the track is crowded For the later entry enterprises, it needs to be considered calmly and carefully to see if they have unique advantages Potential can have a place in it Such a variety is a comprehensive competition for the time to market, price, approved indications, sales promotion, etc of the enterprise's drugs, and may gradually be reduced to the competition among the head companies Who will become the best domestic product of PD-1 / L1 McAb, we will wait and see Data source: as a long-term development enterprise, CITIC construction securities tumor immune agonist antibody or the next hot spot can never live on only one variety, platform and pipeline are the most important So, after PD-1 / L1 carnival, what's the next move? According to relevant analysis, after PD-1, a new generation of tumor immune checkpoint agonists may become another place for domestic innovative enterprises to fight In this regard, Xinda biology, Tianyan pharmaceutical, Dingfu target, mabos, clover, Lijin and other enterprises with unique technology platforms have taken the lead in the antibody layout of tumor immune agonists The official website of Xinda biology shows that the phase I study of ibi101 single drug or combination of xindili mAb in the treatment of advanced cancer patients is in progress, which is also the first drug to enter the clinical practice in China; the phase I clinical trial of adg106 in the product line of Tianyan pharmaceutical in the treatment of advanced relapse and metastasis, refractory solid tumor and non Hodgkin's lymphoma is in progress in China and the United States; As the enterprise with the largest distribution of immunoagonist products, Dingfu target has 5 products under research; Lijin bio relies on its world leading cross-linked antibody technology platform and optimized stimulating antibody xlinkabtm (cross-linked antibody TM), and has two related antibodies under research, namely, CD40 and CD137 agonists; Scb-333 (4-1bbl-rrimer) is re developed in the biological product line of clover It has the biological activity of natural ligand and optimized pharmacokinetic characteristics, which can avoid the toxicity of stimulating 4-1BB monoclonal antibody The heat of immunocytotherapy should not be underestimated when the cell therapy standing at the tuyere puts aside the antibody of immunosuppressant / agonist Of course, this field is not perfect at present, facing some problems, such as the inhibition of tumor microenvironment, the lack of tumor specific antigen, the poor immunotherapy, etc., at the same time, there are some new solutions emerging, such as the combination with PD-1 / L1, double target car-t cells, etc According to the statistics of the American Cancer Institute (CRI), as of February 2018, there are 404 car-t projects in clinical trials worldwide According to the latest data (as of May 2019), China has become the country with the largest number of car-t clinical trials in the world with 225 items According to the distribution of the targets, the proportion of car-t clinical trials targeting cd-19 in China is more than 40%, but BCMA is less than CD20, CD22 and GPC3, accounting for only 5% By June 2019, CDE has received more than 30 ind applications for car-t therapy Among them, Nanjing legend, Hengrun Dashen, Mingju biology, Shanghai Keji, zhiyinhe and Fosun kaitin applied to enter the drug validation clinical trial stage, and the early clinical results are exciting Lcar-838m cell preparation of Nanjing legend biology is the first car-t product declared by drug in China, targeting BCMA According to the data reported at present, lcar-838m is effective in the treatment of relapsed or refractory multiple myeloma, with very high potential value; Jwcar029 (CD19 targeting chimeric antigen receptor T cell) is the first car-t product targeting CD19 in China Ten patients with relapsed and refractory B cell non Hodgkin's lymphoma were recruited in phase I clinical practice The objective remission rate of six patients reached 100% 29 days after treatment, indicating its effectiveness and safety GPC-3 Car modified autologous T cells are the first car-t products for HCC in the world, while Shanghai youcadi biology is the company with the largest number of applications In 2019, when the new antigen vaccine begins to stand in the wind, some cell therapy companies will have differentiated and innovative positioning, and many companies will begin to lay out the research of new antigen vaccine to strengthen its technical barriers At present, the industry chain of new antigen based therapy, especially new antigen vaccine, has been formed in China There are about 20 companies that are conducting research in the field of new antigen and have information to be verified, and more than 10 clinical trials are in progress Among them, Haixin Co., Ltd is the first nmpa approved DC immunotherapy project "antigen sensitized human dendritic cells (APDC) for the treatment of metastatic large intestine" "Cancer" has entered the stage of phase III clinical research In addition, four of them are in the phase I clinical stage, including xingqiyuan, Si microorganism, Likang biology and jinuoyin, adakang, aimukang, Anjie biology, Lilai, Suozhen biology and yuce biology Among the more than 20 enterprises, it is worth noting that Siwei (Shanghai) Technology Co., Ltd is the first (currently the only) platform enterprise (LPP / mRNA?) in China for mRNA drug development and production Founded in May 2016 and financed by 10 million rounds a in 2018, the founder team includes Professor Kang Dingguo (MD Anderson Cancer Center life Professor, director of Department of pharmacology and clinical treatment of Roswell cancer center, AAAs follow / fellow / Academician of American Association for the advancement of Science) and Professor Shen Haifa (Associate Professor of Houston Health Science Hospital of Cornell University and famous cancer nano) Medical expert / LPP / mRNA? Technical patent owner), whose products are mainly involved in the field of mRNA individualized cancer vaccine, mRNA infectious disease vaccine, protein deficiency disease mRNA medicine and genetic disease mRNA medicine treatment In May 2019, the first personalized tumor vaccine encoding new antigens for the treatment of advanced malignant solid tumors was registered in the Oriental Hospital Affiliated to Tongji University for clinical trials Source: yuce biological concluded that the phrase "mass entrepreneurship, mass innovation" is very consistent with the current situation in the field of tumor immunotherapy in China Of course, thanks to this kind of assistance, compared with traditional drugs, China has a small gap with developed countries in tumor immunotherapy, and the level of research and development is gradually in line with the world Despite a small number of leading enterprises, the number of start-ups is quite considerable Many think that they can rely on a single product to go on sale for 20 billion yuan The company is listed on the market However, it is well known that the R & D cycle of innovative drugs is long, the investment is high, and the risk is high Therefore, for many enterprises, the positioning is very important They only focus on pre clinical research and then wait for the opportunity to sell / transfer (of course Whether the precursor is a valuable project) or a product to be listed, create its own marketing team, and realize the integration of R & D, production, quality management and sales is the first thing to be clear Moreover, innovation is particularly important Only with clear uniqueness and advantages, can we find a blood path in the market Compared with the mass investment in PD-1 / L1, it may have broad development space in the fields of adoptive cell therapy and immunomodulators targeting immune cells Finally, we hope that more advanced technologies will emerge,