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    Home > Medical News > Medical World News > ADC medicine PK! Rongchang biological rc48 indication dobiotai bat8001 has made rapid progress

    ADC medicine PK! Rongchang biological rc48 indication dobiotai bat8001 has made rapid progress

    • Last Update: 2019-10-23
    • Source: Internet
    • Author: User
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    Original: Vegetables Recently, rc48, a blockbuster ADC drug independently developed by Rongchang biology, has launched another clinical trial to treat patients with HER2 overexpression type advanced cholangiocarcinoma who failed in chemotherapy with single drug first-line therapy As of October 21, rc48 has five indications in research, including urothelial cancer, breast cancer, gastric cancer, lung cancer and biliary cancer, which has become the ADC drug with the most indications in research in China (source: drug clinical trial registration and information publicity platform) At present, the FDA has approved 6 kinds of antibody drug conjugate (ADC) to go on the market, most of which are back-line therapy (source: FDA) Among them, Mylotarg is the first ADC drug on the market in the world, which was approved by FDA in 2000 for the treatment of acute myeloid leukemia However, due to its lethal cytotoxicity, Pfizer took the initiative to withdraw from the market after purchasing Wyeth in 2010, and then went on the market again in 2017 with the approval of FDA Roche's kadcyla has met the treatment needs of breast cancer patients who are resistant to first-line treatment after being put on the market, so it has performed well in ADC drugs that have been put on the market In 2018, its sales reached 979 million Swiss francs (about US $1.001 billion) With the development of technology in recent years, there are more than 80 ADC drugs in clinical stage overseas, 20 of which have entered phase II / III It is expected that more ADC drugs will be approved for market in the future At present, there is no ADC drug on the market in China, and HER2 is the most targeted drug in ADC research Roche's enmettrazumab, namely kadcyla, has submitted an application for listing in March 2019, while baiaotai's bat8001 has entered phase III, which belongs to the fastest progress of domestic ADC drugs, and more than ten other drugs have entered the clinical stage ADC drugs entering clinical stage Ⅱ and above in China (source: baiaotai prospectus) Other companies include cmet-adc, her2-adc, lizumab, Fosun, f0002-adc, myako, Kelun, Dongyao, Jiahe, Sansheng, Qide, Zhaohua, Haizheng, Shiyao group, new idea, DUOXI, Sichuan Baili, Trez, mabtec h Norling and so on are in stage I or earlier Rc48 is an antibody coupled drug (ADC) independently developed by Rongchang biology It is composed of new HER2 monoclonal antibody, cathepsin cleavable linker, methylreoxetine e (MMAE) and cytotoxic payload It is intended to be used in the treatment of HER2 positive solid tumors Rc48 is the first ADC drug approved by nmpa in China At the 55th ASCO annual meeting, Rongchang biology released the preliminary results of the research titled "rc48-adc treatment of HER2 positive local advanced or metastatic urothelial cancer phase II clinical trial" The results showed that in 43 patients with second-line and multiline urothelial cancer who received rc48 treatment, the confirmed objective remission rate (gorr) was as high as 51.2%, and the disease control rate (DCR) was as high as 90.7% Urothelial carcinoma is a common malignant tumor in the world, which seriously endangers human life and health Urothelial carcinoma can be divided into renal pelvis carcinoma, ureter carcinoma, bladder carcinoma and urethra carcinoma Statistics show that more than 90% of urothelial tumors originate from bladder, 8% from renal pelvis, and the rest 2% from ureter and urethra Take the bladder cancer, which accounts for the largest proportion, as an example In 2018, there were 549000 new cases and 200000 deaths in the world; in China, there were 82000 new cases and 38000 deaths At present, no drugs for HER2 positive urothelial cancer have been approved for marketing at home and abroad Rc48 achieved a significant breakthrough in the above results, not only with a high effective rate, but also significantly extended the survival period of patients after failure of first-line treatment, which filled this huge medical demand Industry insiders said that Rongchang biological is ready to submit conditional approval for the listing of urothelial cancer Bat8001 skipped phase II clinical treatment and became the first domestic ADC drug to enter phase III clinical treatment in China The development progress of bat8001 exceeded Rongchang biological rc-48 Bat8001 is the first ADC drug developed by baiaotai It is covalently linked by recombinant human anti erbB2 / neu / HER2 monoclonal antibody and the independently developed linker (6-maleimide hexanoic acid) - toxin complex The preclinical research results show that bat8001 has a significant inhibitory effect on the tumor proliferation with high expression of HER2 At present, phase III clinical trials of HER2 positive advanced breast cancer are being carried out in China It is worth mentioning that Roche's kadcyla has submitted its listing application to nmpa in March 2019, and is also used to treat HER2 positive breast cancer In addition, the clinical trial of bat8001 combined with bat1306 in the treatment of HER2 positive advanced solid tumors has also entered Ib / IIA stage Because HER2 is highly expressed in breast cancer and gastric cancer, the indications of ADC drug development are mostly concentrated in these two fields In addition to urothelial carcinoma, the clinical trial of rc48 in the treatment of HER2 positive advanced breast cancer has also entered phase II According to the 2019 national cancer report, according to the ranking of the number of patients, breast cancer ranks first in the incidence of female cancer in China HER2 is a member of human epidermal growth factor receptor (EGFR) family protein HER2 positive breast cancer accounts for about 20% - 25% of all breast cancers This type of breast cancer has high invasiveness and poor prognosis According to frost Sullivan report, from 2014 to 2018, the number of patients with advanced HER2 positive breast cancer in China increased from 15700 to 16900, with a compound annual growth rate of 1.8% It is expected that the number of patients with advanced HER2 positive breast cancer in China will reach 18200 by 2023, and then the number of patients will continue to grow at a compound annual growth rate of 1.0%, reaching 19600 by 2030 (source: frost Sullivan report) To learn more about ADC principles, read the following sections According to the prediction of American news agency, the ADC drug market will reach 9.93 billion US dollars in 2025, with a compound annual growth rate of 25.9% Basic principle: The antibody drug conjugate (ADC) is obtained by the coupling of mAb and payload, and the stability of linker is the key point of ADC (source: protein & cell) Compared with the traditional monoclonal antibody drugs, ADC drugs have not only the ADCC (antibody dependent cytotoxic effect) and CDC (complement dependent cytotoxic effect) of antibody part, but also the extra cytotoxic effect of tumor cells When the antibody and the tumor surface target antigen combine, the tumor cells will produce endocytosis effect on the ADC drugs When the ADC enters the cells, it will decompose under the action of lysosome At this time, the cytotoxic drugs are released in the cells, thus playing a role of killing cells Therefore, the serum safety and stability of ADC drugs are the core of drug development In addition, the affinity of antibody and receptor is not the most important High affinity often reduces the penetration ability of antibody, and specificity is the most important Antibody and target selection: The McAb part of ADC drugs is responsible for the most important targeting role, delivering small molecule compounds to the antigen antibody binding site, so in the development of ADC drugs, the correct antibody is particularly important At present, ADC drugs are modified with humanized monoclonal antibody to reduce ADCC and CDC The appropriate antibody is aimed at the right target Almost all the developed ADC drugs cover the confirmed target The determination of the target basically determines the indications of ADC drugs The following targets have been or are being evaluated by major research institutions to determine whether they are the potential targets of the appropriate ADC drugs Selection of cytotoxic drugs: There are four kinds of cytotoxic drugs coupled with ADC, among which tubulin inhibitors are the mainstream The cytotoxin needs to meet the following conditions: (1) strong water solubility and serum stability; (2) good coupling ability with linker; (3) insensitivity to lysosomal enzyme and degradation reaction; (4) low polymerization effect (source: Journal of drug delivery science and Technology) Connection sub selection: Linkers can be divided into two types: cleavable linker and non cleavable linker, among which cleavable linker is the most commonly used at present According to the principle, linker can be divided into acid sensitive type, glutathione sensitive type and protease sensitive type Acid sensitive type is the current mainstream choice The linker is required to be highly stable in serum, so as to avoid the possibility of Miss target and reduce the side effects Each part of ADC affects the final efficacy of the drug, so the appropriate choice of each part is particularly important Classification:
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