scholarly journals Treatment of Autoimmune Hyperthyroidism in a Murine Model of Graves’ Disease with Tumor Necrosis Factor-Family Ligand Inhibitors Suggests a Key Role for B Cell Activating Factor in Disease Pathology

Endocrinology ◽  
2006 ◽  
Vol 147 (10) ◽  
pp. 4561-4568 ◽  
Author(s):  
Jacqueline A. Gilbert ◽  
Susan L. Kalled ◽  
Jane Moorhead ◽  
Donna M. Hess ◽  
Paul Rennert ◽  
...  
Keyword(s):  
B Cell ◽  
Plasma Cells ◽  
Autoimmune Disorder ◽  
Cell Maturation ◽  
Graves Disease ◽  
Histopathological Analysis ◽  
Specific Receptor ◽  
B Cell Maturation ◽  
B Cell Activating Factor ◽  
B Cell Maturation Antigen

Hyperthyroid Graves’ disease is a common autoimmune disorder mediated by agonistic antibodies to the TSH receptor, termed thyroid stimulating antibodies (TSAbs). Recently members of the TNF superfamily, B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), have been identified along with their receptors, B cell maturation antigen and transmembrane activator and calcium-modulator and cyclophilin ligand interactor, and the BAFF-specific receptor. BAFF is a fundamental B cell survival/maturation factor, and both BAFF and APRIL have been implicated in antibody production. We investigated the effect of interfering with BAFF- and APRIL-mediated signals in an induced model of Graves’ disease by blockade of these factors using soluble decoy receptors. In a therapeutic setting in mice with established hyperthyroidism, we show that blockade of BAFF or BAFF+APRIL with BAFF-specific receptor-Fc and B cell maturation antigen-Fc, respectively, leads to significant reductions in the induced hyperthyroidism. This was supported by a parallel pattern of declining TSAbs in the responding animals. Histopathological analysis of splenic sections from treated animals revealed marked reductions in the B cell follicle regions, but staining with anti-CD138 revealed the persistence of plasma cells. Thus, the reductions in TSAbs in the treated animals were not related to overall plasma cell numbers in the secondary lymphoid organs. Our results are the first to demonstrate attenuation of established hyperthyroidism by therapeutic intervention aimed at autoreactive B cells and indicate that both BAFF and APRIL appear to play important roles in the development and survival of the autoantibody producing cells in this model.

B-lymphocyte-induced maturation protein1 up-regulates the expression of B-cell maturation antigen in mouse plasma cells

2010 ◽  
Vol 37 (8) ◽  
pp. 3747-3755 ◽  
Author(s):  
Shaoli Deng ◽  
Tao Yuan ◽  
Xiaoxing Cheng ◽  
Rui Jian ◽  
Jing Jiang
Keyword(s):  
B Cell ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Cell Maturation ◽  
Mouse Plasma ◽  
B Cell Maturation ◽  
B Cell Maturation Antigen

Binding of B-cell maturation antigen to B-cell activating factor induces survival of multiple myeloma cells by activating Akt and JNK signaling pathways

2016 ◽  
Vol 34 (2) ◽  
pp. 104-110 ◽  
Author(s):  
Xianjuan Shen ◽  
Yuehua Guo ◽  
Jing Qi ◽  
Wei Shi ◽  
Xinhua Wu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Signaling Pathways ◽  
Cell Maturation ◽  
Myeloma Cells ◽  
Jnk Signaling ◽  
B Cell Maturation ◽  
B Cell Activating Factor ◽  
B Cell Maturation Antigen

scholarly journals B-Cell Maturation Antigen, A Proliferation-Inducing Ligand, and B-Cell Activating Factor Are Candidate Mediators of Spinal Cord Injury-Induced Autoimmunity

2013 ◽  
Vol 30 (6) ◽  
pp. 434-440 ◽  
Author(s):  
Jonah W. Saltzman ◽  
Ricardo A. Battaglino ◽  
Loise Salles ◽  
Prateek Jha ◽  
Supreetha Sudhakar ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
B Cell ◽  
Cell Maturation ◽  
B Cell Maturation ◽  
B Cell Activating Factor ◽  
Cord Injury ◽  
Antigen A ◽  
B Cell Maturation Antigen

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.

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.

Belantamab mafodotin in the treatment of relapsed or refractory multiple myeloma

2020 ◽  
Vol 16 (34) ◽  
pp. 2783-2798 ◽  
Author(s):  
Semira Sheikh ◽  
Eyal Lebel ◽  
Suzanne Trudel
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Plasma Cells ◽  
Safety Data ◽  
Unmet Need ◽  
Cell Maturation ◽  
Antibody Drug Conjugate ◽  
Refractory Multiple Myeloma ◽  
B Cell Maturation ◽  
B Cell Maturation Antigen

Multiple myeloma remains an incurable disease, with a large proportion of patients in the relapsed/refractory setting often unable to achieve durable responses. Novel, well-tolerated and highly effective therapies in this patient population represent an unmet need. Preclinical studies have shown that B-cell maturation antigen is nearly exclusively expressed on normal and malignant plasma cells, thereby identifying it as a highly selective target for immunotherapeutic approaches. Belantamab mafodotin (GSK2857916, belamaf) is a first-in-class antibody–drug conjugate directed at B-cell maturation antigen and has shown promising activity in clinical trials. In this review, we provide an overview of belantamab mafodotin as a compound and present the available clinical efficacy and safety data in the treatment of relapsed/refractory multiple myeloma.

Correlation of B cell activating factor, B cell maturation antigen, and other cytokines profile with inhibitor status in hemophilia A

2019 ◽  
Vol 44 (2) ◽  
pp. 149
Author(s):  
Nuzhat Husain ◽  
Sanya Arshad ◽  
Vandana Tiwari ◽  
Azfar Neyaz ◽  
NamrataP Awasthi
Keyword(s):  
B Cell ◽  
Hemophilia A ◽  
Cell Maturation ◽  
Factor B ◽  
B Cell Maturation ◽  
B Cell Activating Factor ◽  
B Cell Maturation Antigen

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 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 Maturation of Marginal Zone and Follicular B Cells Requires B Cell Activating Factor of the Tumor Necrosis Factor Family and Is Independent of B Cell Maturation Antigen

2001 ◽  
Vol 194 (11) ◽  
pp. 1691-1698 ◽  
Author(s):  
Pascal Schneider ◽  
Hisakazu Takatsuka ◽  
Anne Wilson ◽  
Fabienne Mackay ◽  
Aubry Tardivel ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Tumor Necrosis ◽  
Marginal Zone ◽  
Cell Maturation ◽  
Soluble Form ◽  
B Cell Maturation ◽  
B Cell Activating Factor ◽  
Necrosis Factor ◽  
B Cell Maturation Antigen

B cells undergo a complex series of maturation and selection steps in the bone marrow and spleen during differentiation into mature immune effector cells. The tumor necrosis factor (TNF) family member B cell activating factor of the TNF family (BAFF) (BLyS/TALL-1) plays an important role in B cell homeostasis. BAFF and its close homologue a proliferation-inducing ligand (APRIL) have both been shown to interact with at least two receptors, B cell maturation antigen (BCMA) and transmembrane activator and cyclophilin ligand interactor (TACI), however their relative contribution in transducing BAFF signals in vivo remains unclear. To functionally inactivate both BAFF and APRIL, mice transgenic for a soluble form of TACI were generated. They display a developmental block of B cell maturation in the periphery, leading to a severe depletion of marginal zone and follicular B2 B cells, but not of peritoneal B1 B cells. In contrast, mice transgenic for a soluble form of BCMA, which binds APRIL, have no detectable B cell phenotype. This demonstrates a crucial role for BAFF in B cell maturation and strongly suggests that it signals via a BCMA-independent pathway and in an APRIL-dispensable way.

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