B-cell maturation antigen explained

Symbol:	BCMA-Tall_bind
BCMA TALL-1 binding domain
Pfam:	PF09257
Interpro:	IPR015337
Scop:	1oqd

B-cell maturation antigen (BCMA or BCM), also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17), is a protein that in humans is encoded by the TNFRSF17 gene.

TNFRSF17 is a cell surface receptor of the TNF receptor superfamily which recognizes B-cell activating factor (BAFF).^{[1] [2] [3]}

Serum B-cell maturation antigen (sBCMA) is the cleaved form of BCMA, found at low levels in the serum of normal patients and generally elevated in patients with multiple myeloma (MM).^[4]

Function

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is preferentially expressed in mature B lymphocytes, and may be important for B cell development and autoimmune response. This receptor has been shown to specifically bind to the tumor necrosis factor (ligand) superfamily, member 13b (TNFSF13B/TALL-1/BAFF), and to lead to NF-kappaB and MAPK8/JNK activation. This receptor also binds to various TRAF family members, and thus may transduce signals for cell survival and proliferation.

Interactions

TNFRSF17 has been shown to interact with the B-cell activating factor TNFSF13B.^{[5] [6]} A conserved domain at the N-terminus, BCMA TALL-1 binding domain, is required for binding to the TNFSF13B.

Clinical significance

TNFRSF17 is implicated in leukemia, lymphomas, and multiple myeloma^[7] (see the "Mitelman Database" ^[8] and the Atlas of Genetics and Cytogenetics in Oncology and Haematology,^[9]).

As a drug target

An antibody-drug conjugate Belantamab mafodotin (GSK2857916) has evaluated in patients with relapsed/refractory multiple myeloma.^[10] Belantamab mafodotin was approved in the United States in August 2020 for the treatment of patients with relapsed or refractory multiple myeloma who have received at least four prior therapies.^[11]

Chimeric antigen receptor (CAR) T cells have emerged as an important therapy for multiple myeloma after first reports in preclinical and phase I clinical studies.^{[12] [13]} A Phase 1b/2 study of JNJ-4528, a CAR-T cell therapy directed against BCMA in myeloma patients refractory to a proteasome inhibitor or immunomodulatory drug, and who had received an anti-CD38 antibody has been completed.^[14]

ALLO-715 is a CAR-T therapy by Allogene Therapeutics that targets B-cell maturation antigen (BCMA).^[15], it is undergoing clinical trials for the treatment of multiple myeloma. On 21 April 2021, the FDA granted Regenerative Medicine Advanced Therapy status to ALLO-715.^[16] ALLO-715 is being investigated at Memorial Sloan Kettering Cancer Center and the Mayo Clinic^[17] as part of the UNIVERSAL trial for multiple myeloma, on its own and in conjunction with the selective gamma secretase inhibitor nirogacestat.^[18]

Further reading

• Treml LS, Crowley JE, Cancro MP . BLyS receptor signatures resolve homeostatically independent compartments among naïve and antigen-experienced B cells . Seminars in Immunology . 18 . 5 . 297–304 . October 2006 . 16919470 . 10.1016/j.smim.2006.07.001 .
• Mackay F, Leung H . The role of the BAFF/APRIL system on T cell function . Seminars in Immunology . 18 . 5 . 284–289 . October 2006 . 16931039 . 10.1016/j.smim.2006.04.005 .
• Gras MP, Laâbi Y, Linares-Cruz G, Blondel MO, Rigaut JP, Brouet JC, Leca G, Haguenauer-Tsapis R, Tsapis A . 6 . BCMAp: an integral membrane protein in the Golgi apparatus of human mature B lymphocytes . International Immunology . 7 . 7 . 1093–1106 . July 1995 . 8527407 . 10.1093/intimm/7.7.1093 .
• Loftus BJ, Kim UJ, Sneddon VP, Kalush F, Brandon R, Fuhrmann J, Mason T, Crosby ML, Barnstead M, Cronin L, Deslattes Mays A, Cao Y, Xu RX, Kang HL, Mitchell S, Eichler EE, Harris PC, Venter JC, Adams MD . 6 . Genome duplications and other features in 12 Mb of DNA sequence from human chromosome 16p and 16q . Genomics . 60 . 3 . 295–308 . September 1999 . 10493829 . 10.1006/geno.1999.5927 .
• Gross JA, Johnston J, Mudri S, Enselman R, Dillon SR, Madden K, Xu W, Parrish-Novak J, Foster D, Lofton-Day C, Moore M, Littau A, Grossman A, Haugen H, Foley K, Blumberg H, Harrison K, Kindsvogel W, Clegg CH . 6 . TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease . Nature . 404 . 6781 . 995–999 . April 2000 . 10801128 . 10.1038/35010115 . 4323357 . 2000Natur.404..995G .
• Hatzoglou A, Roussel J, Bourgeade MF, Rogier E, Madry C, Inoue J, Devergne O, Tsapis A . 6 . TNF receptor family member BCMA (B cell maturation) associates with TNF receptor-associated factor (TRAF) 1, TRAF2, and TRAF3 and activates NF-kappa B, elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase . Journal of Immunology . 165 . 3 . 1322–1330 . August 2000 . 10903733 . 10.4049/jimmunol.165.3.1322 . free .
• Shu HB, Johnson H . B cell maturation protein is a receptor for the tumor necrosis factor family member TALL-1 . Proceedings of the National Academy of Sciences of the United States of America . 97 . 16 . 9156–9161 . August 2000 . 10908663 . 16838 . 10.1073/pnas.160213497 . free . 2000PNAS...97.9156S .
• Yu G, Boone T, Delaney J, Hawkins N, Kelley M, Ramakrishnan M, McCabe S, Qiu WR, Kornuc M, Xia XZ, Guo J, Stolina M, Boyle WJ, Sarosi I, Hsu H, Senaldi G, Theill LE . 6 . APRIL and TALL-I and receptors BCMA and TACI: system for regulating humoral immunity . Nature Immunology . 1 . 3 . 252–256 . September 2000 . 10973284 . 10.1038/79802 . 6799584 .
• Kawasaki A, Tsuchiya N, Fukazawa T, Hashimoto H, Tokunaga K . Presence of four major haplotypes in human BCMA gene: lack of association with systemic lupus erythematosus and rheumatoid arthritis . Genes and Immunity . 2 . 5 . 276–279 . August 2001 . 11528522 . 10.1038/sj.gene.6363770 . 12315457 .
• Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W, Gross JA, Greipp PR, Jelinek DF . 6 . Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival . Blood . 103 . 2 . 689–694 . January 2004 . 14512299 . 10.1182/blood-2003-06-2043 . free .
• Hymowitz SG, Patel DR, Wallweber HJ, Runyon S, Yan M, Yin J, Shriver SK, Gordon NC, Pan B, Skelton NJ, Kelley RF, Starovasnik MA . 6 . Structures of APRIL-receptor complexes: like BCMA, TACI employs only a single cysteine-rich domain for high affinity ligand binding . The Journal of Biological Chemistry . 280 . 8 . 7218–7227 . February 2005 . 15542592 . 10.1074/jbc.M411714200 . free .
• Bellucci R, Alyea EP, Chiaretti S, Wu CJ, Zorn E, Weller E, Wu B, Canning C, Schlossman R, Munshi NC, Anderson KC, Ritz J . 6 . Graft-versus-tumor response in patients with multiple myeloma is associated with antibody response to BCMA, a plasma-cell membrane receptor . Blood . 105 . 10 . 3945–3950 . May 2005 . 15692072 . 1895080 . 10.1182/blood-2004-11-4463 .
• Hendriks J, Planelles L, de Jong-Odding J, Hardenberg G, Pals ST, Hahne M, Spaargaren M, Medema JP . 6 . Heparan sulfate proteoglycan binding promotes APRIL-induced tumor cell proliferation . Cell Death and Differentiation . 12 . 6 . 637–648 . June 2005 . 15846369 . 10.1038/sj.cdd.4401647 . free .
• Chiu A, Xu W, He B, Dillon SR, Gross JA, Sievers E, Qiao X, Santini P, Hyjek E, Lee JW, Cesarman E, Chadburn A, Knowles DM, Cerutti A . 6 . Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL . Blood . 109 . 2 . 729–739 . January 2007 . 16960154 . 1785096 . 10.1182/blood-2006-04-015958 .
• Smirnova AS, Andrade-Oliveira V, Gerbase-DeLima M . Identification of new splice variants of the genes BAFF and BCMA . Molecular Immunology . 45 . 4 . 1179–1183 . February 2008 . 17825416 . 10.1016/j.molimm.2007.07.028 .

Notes and References

1. Laâbi Y, Gras MP, Carbonnel F, Brouet JC, Berger R, Larsen CJ, Tsapis A . A new gene, BCM, on chromosome 16 is fused to the interleukin 2 gene by a t(4;16)(q26;p13) translocation in a malignant T cell lymphoma . The EMBO Journal . 11 . 11 . 3897–3904 . November 1992 . 1396583 . 556899 . 10.1002/j.1460-2075.1992.tb05482.x .
2. Laabi Y, Gras MP, Brouet JC, Berger R, Larsen CJ, Tsapis A . The BCMA gene, preferentially expressed during B lymphoid maturation, is bidirectionally transcribed . Nucleic Acids Research . 22 . 7 . 1147–1154 . April 1994 . 8165126 . 523635 . 10.1093/nar/22.7.1147 .
3. Web site: Entrez Gene: TNFRSF17 tumor necrosis factor receptor superfamily, member 17.
4. Maglione PJ, Ko HM, Tokuyama M, Gyimesi G, Soof C, Li M, Sanchez E, Chen H, Radigan L, Berenson J, Cunningham-Rundles C . 6 . Serum B-Cell Maturation Antigen (BCMA) Levels Differentiate Primary Antibody Deficiencies . The Journal of Allergy and Clinical Immunology. In Practice . 8 . 1 . 283–291.e1 . January 2020 . 31430592 . 6980522 . 10.1016/j.jaip.2019.08.012 .
5. Liu Y, Hong X, Kappler J, Jiang L, Zhang R, Xu L, Pan CH, Martin WE, Murphy RC, Shu HB, Dai S, Zhang G . 6 . Ligand-receptor binding revealed by the TNF family member TALL-1 . Nature . 423 . 6935 . 49–56 . May 2003 . 12721620 . 10.1038/nature01543 . 4373708 . free . 2003Natur.423...49L .
6. Shu HB, Johnson H . B cell maturation protein is a receptor for the tumor necrosis factor family member TALL-1 . Proceedings of the National Academy of Sciences of the United States of America . 97 . 16 . 9156–9161 . August 2000 . 10908663 . 16838 . 10.1073/pnas.160213497 . free . 2000PNAS...97.9156S .
7. Web site: TNFRSF17 (tumor necrosis factor receptor superfamily, member 17). atlasgeneticsoncology.org.
8. Web site: Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer. 2015-01-29. 2016-05-25. https://web.archive.org/web/20160525153807/http://cgap.nci.nih.gov/Chromosomes/Mitelman. dead.
9. Web site: Atlas of Genetics and Cytogenetics in Oncology and Haematology. atlasgeneticsoncology.org.
10. Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari A, Abdallah AO, Callander N, Lendvai N, Sborov D, Suvannasankha A, Weisel K, Karlin L, Libby E, Arnulf B, Facon T, Hulin C, Kortüm KM, Rodríguez-Otero P, Usmani SZ, Hari P, Baz R, Quach H, Moreau P, Voorhees PM, Gupta I, Hoos A, Zhi E, Baron J, Piontek T, Lewis E, Jewell RC, Dettman EJ, Popat R, Esposti SD, Opalinska J, Richardson P, Cohen AD . 6 . Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study . The Lancet. Oncology . 21 . 2 . 207–221 . February 2020 . 31859245 . 10.1016/s1470-2045(19)30788-0 . 209425201 .
11. Baines AC, Ershler R, Kanapuru B, Xu Q, Shen G, Li L, Ma L, Okusanya OO, Simpson NE, Nguyen W, Theoret MR, Pazdur R, Gormley NJ . 6 . FDA Approval Summary: Belantamab Mafodotin for Patients with Relapsed or Refractory Multiple Myeloma . Clinical Cancer Research . 28 . 21 . 4629–4633 . November 2022 . 35736811 . 9633344 . 10.1158/1078-0432.CCR-22-0618 .
12. Carpenter RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S, Gress RE, Hakim FT, Kochenderfer JN . 6 . B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma . Clinical Cancer Research . 19 . 8 . 2048–2060 . April 2013 . 23344265 . 10.1158/1078-0432.CCR-12-2422 . 3630268 .
13. Ali SA, Shi V, Maric I, Wang M, Stroncek DF, Rose JJ, Brudno JN, Stetler-Stevenson M, Feldman SA, Hansen BG, Fellowes VS, Hakim FT, Gress RE, Kochenderfer JN . 6 . T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma . Blood . 128 . 13 . 1688–1700 . September 2016 . 27412889 . 10.1182/blood-2016-04-711903 . 5043125 .
14. Madduri D, Usmani SZ, Jagannath S, Singh I, Zudaire E, Yeh TM, Allred AJ, Banerjee A, Goldberg JD, Schecter JM, Zhuang S . 6 . 2019-11-13. Results from CARTITUDE-1: A Phase 1b/2 Study of JNJ-4528, a CAR-T Cell Therapy Directed Against B-Cell Maturation Antigen (BCMA), in Patients with Relapsed and/or Refractory Multiple Myeloma (R/R MM) . Blood . en . 134 . Supplement_1 . 577 . 10.1182/blood-2019-121731 . 209265279 . 0006-4971 . free.
15. Sommer C, Boldajipour B, Valton J, Galetto R, Bentley T, Sutton J, Ni Y, Leonard M, Van Blarcom T, Smith J, Chaparro-Riggers J . 2018-11-29. ALLO-715, an Allogeneic BCMA CAR T Therapy Possessing an Off-Switch for the Treatment of Multiple Myeloma. Blood. 132. Supplement 1. 591. 10.1182/blood-2018-99-119227. 0006-4971. free.
16. Web site: FDA Grants RMAT Designation to ALLO-715 for Relapsed/Refractory Multiple Myeloma . 2022-05-10 . OncLive . 21 April 2021 . en.
17. Web site: Safety and Efficacy of ALLO-715 and ALLO-647 BCMA Allogenic CAR T Cells in Adults With Relapsed or Refractory Multiple Myeloma (UNIVERSAL) . 2022-05-10 . Mayo Clinic . en.
18. Web site: Taylor NP . 2020-12-07 . ASH: Allogene's off-the-shelf CAR-T posts 60% response rate in fiercely competitive BCMA field . 2022-05-10 . Fierce Biotech . en.