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Immuno-Oncology target|BCMA (1)Time:2020-09-30

 

This year, a number of news were reported in BCMA targeted therapeutic drug development field, including FDA initial rejection of the NDA application of Ide-cel (bb2121, BCMA-CAR-T product) jointly developed by Bristol-Myers Squibb (BMS) and Bluebird Bio (Bluebird Bio), and then the NDA resubmission of Ide-cel got FDA priority review, on the other front, GlaxoSmithKline (GSK)’s Blenrep (GSK2857916, BCMA-ADC product) was approved by FDA for marketing..……

 

Figure 1:Different BCMA targeted immunotherapies for multiple myeloma [1] 

The level of interest on BCMA targeted immunotherapies has been higher than ever. It is really exciting to see who will obtain the first FDA approval on BCMA CAR-T cell therapy. (Right now, there are more than 110 clinical trials targeted on BCMA worldwide, and more than 70 of them are CAR-T cell therapies [2]) 

BCMA and MM

TNFRSF17 is a  member of the tumor necrosis factor receptor (TNFR) family, also known as B Cell maturation antigen (BCMA or BCM) or CD269. The receptor is mainly expressed on the surface of mature B lymphocytes and plasma cells, and is a marker protein of B lymphocyte maturation. B cell activation factor (BAFF) and proliferation-inducing ligand (APRIL) are the main ligands of BCMA. They interact with BCMA to transmit cell stimulating signals, activate TRAF-dependent NF-κB and JNK pathways, and increase the proliferation and survival of B cells rate.

Multiple myeloma (MM, Multiple myeloma) is the second most common hematologic cancer, next to non-Hodgkin's lymphoma. The disease is caused by malignant plasma cells in the bone marrow. In recent years, there are the four major therapeutic treatments for MM including chemotherapy, proteasome inhibitors, immunomodulators and CD38 targeting antibodies. All these treatments can can only alleviate the symptoms of multiple myeloma, but cannot cure the disease. Almost all patients will eventually relapse. MM is considered as an incurable disease, so there is an urgent need for new treatment options [3].

 

Figure 2:The pathophysiological process of MM and the BCMA signal pathway [3]

Comparing with other MM treatment target, BCMA almost exclusively express on mature B lymphocytes and plasma cells, and almost no expression can be detected in other tissue cells. Therefore, BCMA is an ideal target for the treatment of MM .

BCMA targeted immune therapy

Currently three main therapeutic approaches are in development to target on BCMA for MM disease, including chimeric T cell antigen receptor (CAR-T, chimeric antigen receptor T-cell), T-cell binding bispecific antibody (BiTE, Bispecific T- Cell engager) and antibody drug conjugate (ADC, Antibody Drug Conjugate) therapy [4].

CAR-T

 

Figure 3: BCMA-CAR-T treatment [4]

By engineering the patient's T cells in vitro, and then infusing back to MM patient, the anti-BCMA scFv on engineered CAR-T cells can specifically bind BCMA and induce tumor cell death.Related CAR-T pipelines in clinical trials: bb2121 (BMS and bluebird bio), LCAR-B38M (Nanjing LegendBio and Janssen), CT053 (Keji Bio), P-BCMA-101 (Poseida Therapeutics), etc.

BiTE (Bi-specific T-cell Engager)

 

Figure 4:BCMA-BiTE treatment [4]

Anti-BCMA BiTE is a kind of bispecific antibody, one end is an anti-BCMA scFv fragment and the other end fused with an anti-CD3 scFv domain. Therefore, this molecule can recruit T cells to the MM cell and then kill MM cells. Related pipelines in clinical trial: AMG420 (Amgen), etc.

ADC (Antibody drug conjugate)

 

Figure 5:BCMA-ADC therapy [4]

ADC is a cytotoxic molecule conjugated antibody. Upon binding with tumor cells, ADC molecule will be rapidly internalized and degraded. Then the cytotoxic payload will be released to kill tumor cells.   Related products and pipelines in clinical trials for MM treatment: GSK2857916 (GSK), MEDI2228 (MedImmune), etc.  

BCMA targeted immunotherapy market

According to preliminary market report, MM market will be expected to reach $ 28.7 Billion by 2027.[5]. 

 

Figure 6:MM drugs from 2017 to 2027 market conditions [6]

With the addition of anti-BCMA therapy, the MM market structure will also undergo a fundamental change: It is estimated that by 2027,  the sales from eight major market countries (the United States, China, Japan, Germany, the United Kingdom, France, Italy, and the rest of West) will be mostly derived from anti-BCMA therapy (35.5%) and anti-CD38 antibody drugs (30.5%) [6].

Regarding BCMA targeted tumor immunotherapy, whether it is CAR-T, BiTE or ADC therapy, the core thing is to obtain anti-BCMA monoclonal antibodies with good specificity and high affinity .In the next article, we will exhibit how we at DIMA BIOTECH developed a unique set of rabbit DimAbs, and then explore the potential therapeutic potential of these clones by further humanization and construction of BiTE and CAR molecules. 

Here we would like to cooperate with institutions interested on this target to to develop therapeutic solution for MM patients. Currently DIMA can offer a full collection of products for BCMA pre-clinical research, including recombinant BCMA proteins, Biosimilar reference antibodies, Rabbit DimAb Anti-BCMA monoclonal antibodies, and Anti-BCMA bispecific BiTE antibodies. You are welcome to inquire free samples to evaluate.

参考文献:

[1]Shah, N., Chari, A., Scott, E. et al. B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia 2020,34: 985–1005.

[2]https://clinicaltrials.gov/

[3]Cho SF, Anderson KC, Tai YT.Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy[J]. Front Immunol. 2018 Aug 10;9:1821.

[4]Yu B, Jiang T, Liu D.BCMA-targeted immunotherapy for multiple myeloma [J].J Hematol Oncol. 2020 Sep 17;13(1):125.

[5]Wilcock P, Webster R.The multiple myeloma drug market[J].Nat Rev Drug Discov. 2019 Jul;18(8):579-580.

[6]GlobalData: Multiple Myeloma-Global Drug Forecast and Market Analysis to 2027.

 

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