scholarly journals B-Cell Maturation Antigen (BCMA) as a Target for New Drug Development in Relapsed and/or Refractory Multiple Myeloma

2020 ◽  
Vol 21 (15) ◽  
pp. 5192 ◽  
Author(s):  
Hanley N. Abramson
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Types ◽  
Cell Maturation ◽  
New Drug ◽  
B Cell Maturation ◽  
B Cell Maturation Antigen

During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, has approximately doubled the disease’s five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug’s effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T-cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ-68284528.

scholarly journals B-Cell Maturation Antigen (BCMA) As a Target for New Drug Development in Relapsed and/or Refractory Multiple Myeloma

2020 ◽  
Author(s):  
Hanley N. Abramson
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Types ◽  
Cell Maturation ◽  
New Drug ◽  
B Cell Maturation ◽  
B Cell Maturation Antigen

During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, have approximately doubled the disease’s five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug’s effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T-cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ-68284528.

scholarly journals Chimeric antigen receptor T-cell therapies for multiple myeloma

Blood ◽  
2017 ◽  
Vol 130 (24) ◽  
pp. 2594-2602 ◽  
Author(s):  
Lekha Mikkilineni ◽  
James N. Kochenderfer
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Maturation ◽  
Cell Therapies ◽  
B Cell Maturation ◽  
Car T ◽  
B Cell Maturation Antigen

Abstract Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells, so new approaches to treatment are needed. T-cell therapies are a promising approach for treating MM, with a mechanism of action different than those of standard MM treatments. Chimeric antigen receptors (CARs) are fusion proteins incorporating antigen-recognition domains and T-cell signaling domains. T cells genetically engineered to express CARs can specifically recognize antigens. Success of CAR-T cells (CAR-Ts) against leukemia and lymphoma has encouraged development of CAR-T therapies for MM. Target antigens for CARs must be expressed on malignant cells, but expression on normal cells must be absent or limited. B-cell maturation antigen is expressed by normal and malignant plasma cells. CAR-Ts targeting B-cell maturation antigen have demonstrated significant antimyeloma activity in early clinical trials. Toxicities in these trials, including cytokine release syndrome, have been similar to toxicities observed in CAR-T trials for leukemia. Targeting postulated CD19+ myeloma stem cells with anti-CD19 CAR-Ts is a novel approach to MM therapy. MM antigens including CD138, CD38, signaling lymphocyte–activating molecule 7, and κ light chain are under investigation as CAR targets. MM is genetically and phenotypically heterogeneous, so targeting of >1 antigen might often be required for effective treatment of MM with CAR-Ts. Integration of CAR-Ts with other myeloma therapies is an important area of future research. CAR-T therapies for MM are at an early stage of development but have great promise to improve MM treatment.

scholarly journals B-cell maturation antigen (BCMA) in multiple myeloma: the new frontier of targeted therapies

2021 ◽  
Vol 12 ◽  
pp. 204062072198958
Author(s):  
Larysa Sanchez ◽  
Alexandra Dardac ◽  
Deepu Madduri ◽  
Shambavi Richard ◽  
Joshua Richter
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
B Cell ◽  
Targeted Therapies ◽  
Safety Data ◽  
Cell Maturation ◽  
Treatment Modalities ◽  
Cell Therapies ◽  
B Cell Maturation ◽  
B Cell Maturation Antigen

Outcomes of patients with multiple myeloma (MM) who become refractory to standard therapies are particularly poor and novel agents are greatly needed to improve outcomes in such patients. B-cell maturation antigen (BCMA) has become an important therapeutic target in MM with three modalities of treatment in development including antibody–drug conjugates (ADCs), bispecific T-cell engagers (BITEs), and chimeric antigen receptor (CAR) T-cell therapies. Early clinical trials of anti-BCMA immunotherapeutics have demonstrated extremely promising results in heavily pretreated patients with relapsed/refractory MM (RRMM). Recently, belantamab mafodotin was the first anti-BCMA therapy to obtain approval in relapsed/refractory MM. This review summarizes the most updated efficacy and safety data from clinical studies of BCMA-targeted therapies with a focus on ADCs and BITEs. Additionally, important differences among the BCMA-targeted treatment modalities and their clinical implications are discussed.

scholarly journals B-cell Maturation Antigen Is a Promising Target for Adoptive T-cell Therapy of Multiple Myeloma

2013 ◽  
Vol 19 (8) ◽  
pp. 2048-2060 ◽  
Author(s):  
Robert O. Carpenter ◽  
Moses O. Evbuomwan ◽  
Stefania Pittaluga ◽  
Jeremy J. Rose ◽  
Mark Raffeld ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Adoptive T Cell Therapy ◽  
Cell Maturation ◽  
T Cell Therapy ◽  
B Cell Maturation ◽  
Promising Target ◽  
B Cell Maturation Antigen

scholarly journals Chimeric Antigen Receptor-Modified T Cell Therapy in Multiple Myeloma: Beyond B Cell Maturation Antigen

2019 ◽  
Vol 10 ◽  
Author(s):  
Marijke Timmers ◽  
Gils Roex ◽  
Yuedi Wang ◽  
Diana Campillo-Davo ◽  
Viggo F. I. Van Tendeloo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Cell Maturation ◽  
T Cell Therapy ◽  
B Cell Maturation ◽  
B Cell Maturation Antigen

scholarly journals Teclistamab is an active T cell–redirecting bispecific antibody against B-cell maturation antigen for multiple myeloma

2020 ◽  
Vol 4 (18) ◽  
pp. 4538-4549 ◽  
Author(s):  
Kodandaram Pillarisetti ◽  
Gordon Powers ◽  
Leopoldo Luistro ◽  
Alexander Babich ◽  
Eric Baldwin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Bispecific Antibody ◽  
Cell Maturation ◽  
B Cell Maturation ◽  
Xenograft Models ◽  
Rpmi 8226 ◽  
B Cell Maturation Antigen

Abstract B-cell maturation antigen (BCMA), a member of the tumor necrosis factor family of receptors, is predominantly expressed on the surface of terminally differentiated B cells. BCMA is highly expressed on plasmablasts and plasma cells from multiple myeloma (MM) patient samples. We developed a BCMAxCD3 bispecific antibody (teclistamab [JNJ-64007957]) to recruit and activate T cells to kill BCMA-expressing MM cells. Teclistamab induced cytotoxicity of BCMA+ MM cell lines in vitro (H929 cells, 50% effective concentration [EC50] = 0.15 nM; MM.1R cells, EC50 = 0.06 nM; RPMI 8226 cells, EC50 = 0.45 nM) with concomitant T-cell activation (H929 cells, EC50 = 0.21 nM; MM.1R cells, EC50 = 0.1 nM; RPMI 8226 cells, EC50 = 0.28 nM) and cytokine release. This activity was further increased in the presence of a γ-secretase inhibitor (LY-411575). Teclistamab also depleted BCMA+ cells in bone marrow samples from MM patients in an ex vivo assay with an average EC50 value of 1.7 nM. Under more physiological conditions using healthy human whole blood, teclistamab mediated dose-dependent lysis of H929 cells and activation of T cells. Antitumor activity of teclistamab was also observed in 2 BCMA+ MM murine xenograft models inoculated with human T cells (tumor inhibition with H929 model and tumor regression with the RPMI 8226 model) compared with vehicle and antibody controls. The specific and potent activity of teclistamab against BCMA-expressing cells from MM cell lines, patient samples, and MM xenograft models warrant further evaluation of this bispecific antibody for the treatment of MM. Phase 1 clinical trials (monotherapy, #NCT03145181; combination therapy, #NCT04108195) are ongoing for patients with relapsed/refractory MM.

scholarly journals Immunotherapeutic strategies targeting B cell maturation antigen in multiple myeloma

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Yi Fang ◽  
Jian Hou
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Plasma Cells ◽  
Residual Disease ◽  
Hematologic Malignancy ◽  
Therapeutic Strategies ◽  
Cell Maturation ◽  
B Cell Maturation ◽  
Clone Evolution ◽  
B Cell Maturation Antigen

AbstractMultiple myeloma (MM) is the second most common hematologic malignancy, and is characterized by the clonal expansion of malignant plasma cells. Despite the recent improvement in patient outcome due to the use of novel therapeutic agents and stem cell transplantation, all patients eventually relapse due to clone evolution. B cell maturation antigen (BCMA) is highly expressed in and specific for MM cells, and has been implicated in the pathogenesis as well as treatment development for MM. In this review, we will summarize representative anti-BCMA immune therapeutic strategies, including BCMA-targeted vaccines, anti-BCMA antibodies and BCMA-targeted CAR cells. Combination of different immunotherapeutic strategies of targeting BCMA, multi-target immune therapeutic strategies, and adding immune modulatory agents to normalize anti-MM immune system in minimal residual disease (MRD) negative patients, will also be discussed.

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