Targeting B cells: China's antibody-based immune disease program
Last Update: 2020-06-19
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China antibody was first founded in 2001, and its headquarters was established in Hong Kong Science and technology parkAt the beginning of its establishment, the team and capital had a deep Hong Kong backgroundIt's not hard to understandBack then, the mainland's pharmaceutical and health industry was still the God of all kinds of health care productsSome of them can be regarded as innovative drugsFor example, the EBP, which was taken by Shiyao, is still in its infancyIt should be noted that the SFDA has only been established for three years< br / > in comparison, the Chinese antibody configuration born in Hong Kong is luxuriousDrLiang Ruian, the founder of the company, graduated from Oxford University in the United Kingdom, has conducted postdoctoral research at YaleHe once served as the deputy director of molecular biology department and the executive director of biological research and Development Department of a leading antibody drug conjugate company in the United StatesNow he is a member of the biotechnology advisory group of the stock exchange of Hong Kong and a professor of science and technology of the University of science and technology of Hong KongHe has been engaged in molecular immunology for nearly 30 yearsAt that time, another founder, DrKuang Zhiwei, was also a biochemistry engineering expert graduated from the University of Maryland in the United States, and served as the vice president of Hong Kong Institute of biotechnology< br / > many observers have a prejudice that they are fond of the new and dislike the oldIn their hearts, they don't like the technology companies that have been established for a long timeIn fact, many of the biotech companies in Nasdaq have a history of more than ten yearsFor example, dendreon, which was acquired by Sanyo Group with us $800 million in 2015, was listed in Nasdaq as early as 2000< br / > although the R & D direction of a company operating for many years may experience turbulence and adjustment, the accumulated resources such as patents, know how and experience may not be wealthLiang Ruian was selected as a member of the biotechnology advisory group of the Hong Kong Stock Exchange in 2018He is also one of the five major leading project talents announced by Suzhou Industrial Park this year and has been recognized by many partiesAlthough the company has been established for a long time, its appearance is not badIf there are still people who firmly believe that technology companies are cool only when they are new, may I ask: did you refund your ofo deposit? < br / > the pipeline layout of B cell targeted immune diseases < br / > the pipeline layout of Chinese antibody is as follows: < br / > it can be seen that the pipeline layout of Chinese antibody is basically around the autoimmune diseases, especially targeting B lymphocyte, with distinctive featuresThe company's main product is anti-CD22 monoclonal antibodyAt present, the fastest-growing indication of rheumatoid arthritis has entered phase IIIAccording to the company's prospectus, DrLiang Ruian has studied the target of CD22 for more than 25 years and is the first scientist to develop humanized CD22 monoclonal antibodythe population of autoimmune diseases is quite large, with statistics showing that it covers 5%-8% of the population (Jacobson, et al., 1997), including Rheumatic Arthritis (RA), Systemic Lupus Erythematosus (SLE), Sj ö gren's Syndrome (SS), etcUsually, immune diseases show multiple organ damage and other complex clinical indications, and the causes are complex< br / > according to traditional textbooks, immune diseases are mainly caused by abnormal T-cell immune systemHowever, in the past ten years, studies have shown that B-cell dysfunction and hyperactivity are also critical in immune diseases, such as the production of a large number of autoantibodies, the increased risk of B-cell lymphoma, etc< br / > mechanismsadopted by the immune system to prevent emergence of autoimmune B cells, Including cell deletion, receiver editing, internal regulation, and external regulation It is well known that rituxan, which targets CD20 for NHL, was approved for RA treatment of anti TNF α failure in 2006, and belimumab, which targets BLyS for SLE, was just approved for marketing in China < br / > the main target of Chinese antibody sm03 is CD22 CD22 is mainly expressed on the surface of B cells, which is an important B cell receptor It is not expressed on the surface of hematopoietic stem cells, young lymphocytes, plasma cells, etc Therefore, it is also considered as an important target for B cell therapy (including immune diseases and B cell related blood tumors) Different from rituxan, the mAb targeting CD20 can completely eliminate B cells CD22 targeting the surface of B cells mainly inhibits B cell activity through different mechanisms, but does not eliminate B cell population < br / > model for the role of CD22 in regulating BCR / TLR mediated B cell responses to autoantigens, At the same time, it can inhibit IL-6, TNF - α and other cytokines which can promote immune response, and further inhibit the excessive immune response It is believed that these mechanisms may play an important role in the inhibition of autoimmune diseases such as RA and SLE The mechanism of targeting CD22 in the treatment of immune diseases was also seen in the phase II experiment of sm03, the core product of Chinese antibody led by Concord < br / > sm03: new choice of RA treatment targeted by CD22 < br / > according to the company's prospectus, sm03 is the first and only anti-CD22 monoclonal antibody drug used in the clinical stage of rheumatoid arthritis in the world, which is the first drug in research among potential similar targets, It is different from other conventional biological products (such as monoclonal antibodies targeting TNF - α, IL-6, il17 and CD20) used to treat RA Sm03 is currently conducting phase III clinical trials of RA indications in China, and the company plans to complete the recruitment of patients by the end of 2019 < br / > sm03 is a new type of B cell regulatory factor, which can combine CD22 on a specific epitope to induce the co location of CD22 and BCR As shown in the figure below, CD22 promotes the inhibition of BCR mediated signal by CD22 from CIS binding to trans binding co location, so as to regulate B cell activity < br / > in vitro experiments showed that sm03 could inhibit the growth of B lymphocytes, induce apoptosis and ADCC effect, and reduce the depletion of peripheral B cells in vivo < br / > up to now, sm03 has completed 4 clinical trials, and there are still two clinical trials related to RA and NHL in progress in China In these clinical trials, sm03 was used as a single therapy or combined with background standard therapy to evaluate safety, tolerance, PK and clinical activity By the end of 2018, a total of 365 adult patients in six clinical trials had been treated with sm03 Sm03 combined with background methotrexate is effective in the treatment of active RA, which can reduce disease activity, improve clinical symptoms and improve body function Compared with the clinical data published by rituximab and infliximab, sm03 showed better safety in transfusion reaction, serious adverse practice, serious infection and malignant tumor < br / > phase II, conducted in Concorde, assessed the efficacy and safety of sm03 in relation to placebo in patients with moderate to severe RA The results of clinical trials showed that significant ACR20 response was observed in the 12th week At the 24th week, the ACR20 response rate of sm03 treatment group was significantly higher than that of placebo group (65.3% vs 56.9% vs 34%) The acr50 response rate (44.9% vs 29.4% vs 17%) and acr70 response rate (18.4% vs 9.8% vs 4.3%) of sm03 were also higher The 24 week EULAR response rate of sm03 group was higher than that of placebo group (75.5% vs 70.6% vs 40.4%) The number of tenderness joints and swelling joints reported by the patients also improved significantly Many of the early research results of < br / > sm03 have been published The company expects to complete the recruitment of patients for sm03 RA phase III clinical trials by the end of 2019, plans to apply to nmpa for sm03nda for rheumatoid arthritis in the second half of 2020, and plans to start the global development of sm03 through bridging clinical trials in Australia The clinical trials of other indications of sm03, including NHL, SLE and SS, are also in progress, and the senior management of the commercialization team will also arrive before the end of 2019 < br / > sn1011: immune disease development of BTK inhibitors More attention has been paid to the development of BTK inhibitors for tumor indications From the mechanism of action, when B-cell receptor is stimulated, the cascade events will lead to Btk activation, and then lead to a series of events, including: 1) B-cell antigen presentation, B-cell proliferation and release of different cytokines, 2) independent production of autoantibodies, 3) immune complexes against some antigens trigger bone marrow cells through Fc receptor, leading to Btk activation, 4) Cytokines and other inflammatory mediators are released, causing organ damage < br / > sn1011 inhibited the activation of BTK and prevented organ injury grade associated events caused by related autoimmune reactions Sn1011, as low as 1.67mg/kg, effectively inhibited inflammatory response for up to 14 days in the mouse CAIA model for RA In the mouse MRL / lpr lupus erythematosus model, sn1011 has been shown to effectively inhibit the occurrence of disease in a dose-dependent manner < br / > at present, sn1011 has completed all preclinical studies and is ready to start clinical studies in Australia It is planned to complete the phase I FIH administration study of healthy subjects in Australia by the end of 2019, so as to obtain the final study report by the middle of 2020, and submit ind to China National Drug Administration in the fourth quarter of 2019 < br / > RA: China's blue ocean market and drug resistance opportunities < br / > including sm03, rheumatoid arthritis RA is the main indication of several Chinese antibody products In the market segments of the pharmaceutical industry, there are several indications that the west is bright and the East is not bright, and RA is a typical one In the European and American market, RA is the biggest indication besides tumor It has been chased by domestic biosimilar enterprises as the six major varieties of monoclonal antibody in the Red Sea, including Enbrel, REMICADE and Humira, which are all aimed at RA indications, excluding the RA indications approved by rituxan < br / > RA market hasn't been done in China in the past The reason is more complicated The lack of willingness to pay for non fatal diseases is one aspect But what's more, MNC is not very interested in the Chinese market of this indication No matter it's doctor education, access policy or pricing strategy, after all, the low hanging fruit in developed countries has been fed up In this case, local Pharma of China is not willing to follow up < br / > however, the trend in recent years shows that with the price reduction of original research products, the launch of domestic biosimilar products, the improvement of RA diagnosis and the improvement of patients' payment ability and willingness, more and more newly approved biological agents may continue to increase the popularity of RA market < br / > several RA products under development in China are mainly targeted at the treatment of drug-resistant patients with clinical TNF - α The huge sales volume of targeted TNF - α monoclonal antibody drugs is easy to confuse the cognition of this market Although the clinical TNF - α targeted therapy has a significant effect on RA, the market, about 20% to 40% of patients, for TNF - α inhibitor treatment improvement is very limited, ACR20 improvement is less than 20% Some doctors and guidelines will advise patients to replace another TNF - α inhibitor for treatment, but statistics show that after the first TNF - α inhibitor is resistant, the probability of the second TNF - α resistance insufficient response will be significantly increased In view of this, it is imperative to develop new therapeutic drugs for TNF - α inhibitor resistant patients < br / > European response following treatment with one or two TNF inhibitors Data from Navarro et al The company believes that sm03 and other products under development can not only occupy the market of patients with ineffective traditional therapeutic targets and long-term drug resistance, but also occupy the existing market of traditional targets by virtue of the safety advantage shown in phase II clinical practice
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