"CD38" and "BCMA" --- the two main battlegrounds for the development of multiple myeloma drugs.

Multiple myeloma (mm) is a common blood cancer in middle-aged and elderly people. In recent years, the disease has also shown a younger trend. However, public awareness of multiple myeloma is generally low.in the early stage of the disease, the patient may not have any specific symptoms, which may lead to bone pain, bleeding, frequent infection and anemia.in the early stage, the standard treatment of multiple myeloma is chemotherapy, and the common drug is melphalan. However, it usually causes myelosuppression after taking such drugs, and the curative effect is not ideal. The median survival time of patients is 24-36 months, and the five-year survival rate is only about 24%.after treatment, the complete remission rate is only about 5%; even if autologous stem cell transplantation is carried out, the complete remission rate is only 20-30%.these traditional treatment methods are also used to alleviate the disease.with the progress of medicine in recent years, the development of targeted drugs (such as proteasome inhibitors, immunomodulators and antibodies, etc.) has brought a revolution in the treatment of multiple myeloma. Compared with the original treatment scheme, the treatment scheme based on targeted drugs has improved the cure rate and survival rate of patients with multiple myeloma by a big step In the development of targeted drugs for myeloma, the development situation of targeting CD38 and BCMA drugs has gradually formed. The corresponding targeted drugs also show amazing curative effect in multiple myeloma, which greatly changes the treatment status of multiple myeloma.CD38 battlefield CD38 is a surface protein highly expressed in multiple myeloma cells, and is an important therapeutic target in mm and other malignant tumors. The success of two anti-CD38 antibody drugs has fully verified the therapeutic prospect of this target. The development of dual antibody and car-t for this target also has layout.mechanism of action of anti-CD38 antibody on MM cells in November 2015, the world's first targeted CD38 antibody darzalex (jointly developed by Johnson & Johnson and genmab) was approved by FDA and used as a single drug in the fourth line treatment of MM patients.since then, darzalex has been promoted steadily and has been upgraded to the first-line clinical drug for MM patients.and darzalex has become a blockbuster in the field of multiple myeloma, and its annual sales volume has gradually increased. In 2019, the sales volume has reached 2.998 billion US dollars. Now, darzalex has been listed in the United States, the European Union, China, Japan and other countries.△ by targeting CD38, darzalex (daratumumab) can induce cancer cell death through a variety of immune related mechanisms, including complement dependent cytotoxicity, antibody dependent cell-mediated cytotoxicity, antibody dependent phagocytosis and apoptosis.five years after darzalex dominated the market, sarclisa (isatuximab) of Sanofi, the second CD38 monoclonal antibody approved for marketing in the field of multiple myeloma, was approved by the FDA in March this year. In combination with pomalidomide and dexamethasone, sarclisa was used in combination with pomalidomide and dexamethasone, which had previously received at least two treatments (including lenalidomide and proteasome) Inhibitors) in patients with R / RMM.as early as last summer, EMA also accepted the listing application (MAA) of sarclisa treatment R / RMM.it is understood that the price of sarclisa in the United States is US $650 / 100mg and US $3250 / 500mg.the regimen was: 10 mg / kg sarclisa combined with POM DEX, once a week for the first four weeks, and then once every two weeks until disease progression or unacceptable toxicity.△ isatuximab is a chimeric monoclonal antibody targeting CD38, which can trigger a variety of different mechanisms, including promoting apoptosis and regulating immune response.isatuximab has been approved by FDA and EMA for orphan drug treatment of recurrent or refractory multiple myeloma (R / R mm). on June 3, 2020, Sanofi announced that its CD38 monoclonal antibody sarclisa (isatuximab) combined with caffezomib and dexamethasone in the treatment of recurrent multiple myeloma (mm) reached the main end point. the results showed that the combination of sarclisa + caffezomib + dexamethasone significantly reduced the risk of disease progression or death in MM patients by 47%, and showed therapeutic benefits in all subgroups. isatuximab is based on a randomized, multicenter, open label phase III clinical trial called icaria-mm. A total of 307 patients with R / RMM were enrolled. The median number of previous treatment lines for these patients was 3 lines (they had received at least 2 courses of lenalidomide and proteasome inhibitors, but the last treatment failed). in this study, patients were randomly assigned to POM DEX or sarclis combined with POM DEX group. Sarclisa was given by intravenous infusion at a dose of 10mg / kg, once a week for 4 weeks, followed by a 28 day cycle every other week, and then treated with POM DEX. the results showed that sarclisa combined with POM DEX could significantly prolong the progression free survival (PFS) of patients with R / R mm, reaching the primary end point of improving PFS. compared with POM DEX group, the overall response rate (ORR) of sarclisa combined with POM DEX group was 60.4%, and that of POM DEX group was 35.3%. the median progression free survival (PFS) was 11.53 months (vs 6.47 months) in the combined treatment group, showing significant clinical benefits of sarclisa combined with POM DEX. earlier, in order to cope with the market competition of sarclisa, a strong competitor from Sanofi, Johnson & Johnson and genmab have started to further upgrade their equipment. On June 11 last year, Johnson & Johnson and genmab reached an agreement again to jointly promote the development and commercialization of a new generation of CD38 monoclonal antibody. in addition to Johnson & Johnson, MorphoSys, CASI, Takeda, Roche, Tianjing biology, etc. have joined in the development of anti-CD38 drugs. Among them, MorphoSys has made relatively rapid progress. Its CD38 monoclonal antibody mor202 has completed phase II clinical trial. The ORR of this drug combined with lenalidomide and dexamethasone has reached 65%. At present, the drug has entered clinical phase III. 2017 November, the MorphoSys and the MorphoSys have gained the exclusive right to develop and commercialize MOR202 in Greater China (Chinese mainland, Taiwan, Hongkong and Macao). not long ago, Tianjing biological announced MOR202 to complete the first clinical trial of the multi center registered clinical II phase in mainland China at the Institute of Hematology, China Academy of Medical Sciences. in April 2019, CASI pharmaceutical introduced a new CD38 monoclonal antibody cid-103 from black belt therapeutics. Earlier (June 9), the company announced that it had submitted a new drug research application (ind) of cid-103 to the drug and Health Products Administration (MHRA) for the treatment of hematological malignancies including multiple myeloma. Takeda and Roche are still in preclinical stage. in addition to CD38, BCMA target is another battlefield with concentrated firepower for drug development of multiple myeloma. As a new hot target of this disease, BCMA's drug development situation is basically comparable to CD38. At present, car-t therapy, monoclonal antibody, double antibody and ADC drugs targeting BCMA have been developed, and have made good progress Exhibition. immunotherapy based on BCMA has become the second most popular target after CD19 in the current hot car-t therapy field. Among them, idecabagene vicleucel (IDE cel, bb2121) of BMS / Bluebird and jnj-4528 of Johnson / legend are the two bcma-car-t therapies. previously, the European Drug Administration (EMA) has accepted the marketing permission application (MAA) of BMS / Bluebird's idecabagene vicleucel, and Johnson & Johnson / legend biology are also planning to submit jnj-4528 BLA to the FDA in the second half of this year for the treatment of recurrent / refractory multiple myeloma. in addition to car-t therapy, ADC and bispecific antibodies have attracted a lot of attention. At the end of last year, GSK also submitted its application for biological agent license (BLA) for targeting bcma-adc drug belantamab mafodotin to the FDA for the treatment of R / R MM patients. Previously, belantamab mafodotin has been given priority review by FDA. If the review is successful, belantamab will be approved Mafodotin will be the first drug to target BCMA. in addition, amg420, a dual antibody targeting BCMA of Amgen company, has obtained the status of fast track approval authorized by FDA. summary: multiple myeloma is a very difficult blood malignancy. In the years of unremitting efforts, human beings have made no small breakthrough. nowadays, the development of targeted drugs represented by targeted CD38 and BCMA therapy has created a new situation in the treatment of multiple myeloma, significantly improving and broadening the clinical benefits of patients with multiple myeloma. I believe that with the continuous exploration and improvement of clinical treatment, one day, the natural course of multiple myeloma, which is difficult to cure cancer, will be terminated by the medical community. the orr of GlaxoSmithKline bcma-adc combination therapy reached 78% and the listing application of BMS / Bluebird bcma-car-t therapy in the United States was blocked. The European listing application was accepted by EMA and entered the approval process. The complete remission rate of YANGSEN / legend bcma-car-t therapy reached 86%. The current situation of multiple myeloma treatment and the development of antibody drugs targeting BCMA were the first BCMA targeted ADC drug belantamab mafodotin: combined with kylin fucose total knock-out technology of Concord fermentation, Sanofi CD38 antibody isatuximab has been approved by FDA. For submission / reprint, please contact wechat: wz910605 business cooperation contact: welcome to forward and share. 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