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Belimumab

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Belimumab
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetB-cell activating factor
Clinical data
ATC code
  • none
Identifiers
CAS Number

Belimumab (registered name Benlysta previously known as LymphoStat-B), is a fully human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-Lymphocyte stimulator (BLyS), also known as B cell activation factor of the TNF family (BAFF).[1]

The BLyS protein was discovered by researchers from the National Jewish Medical and Research Center and the University of Colorado and announced in 1999. BLyS plays a key role in B lymphocyte differentiation, survival and activation.[2].

Belimumab successfully met the primary endpoints in its phase III clinical trials for Systemic Lupus Erythematosus (SLE).[3] It is currently under fast track review for approval for this application by the FDA with a decision scheduled for December 9, 2010. If approved, Benlysta would be the first new drug to treat Lupus in 50 years. Industry analysts expect the drug to be a blockbuster, with annual sales exceeding 2.2 billion by 2014.[4]

It has undergone phase II clinical trials for rheumatoid arthritis.[5]

Discovery and development

In 1999 protein with immune stimulant properties was called TALL-1[6] and BLyS.[7] In 2003 researchers reported that by using phage display technology, they were able to elicit a remarkably broad array of over 1000 distinct antibodies, half of which inhibited binding of BLyS to its receptor.[8] Later that year, human monoclonal antibody LymphoStat-B, subsequently called belimumab.[9]

Interaction of BLyS with B lymphocytes

Three membrane receptors are concerned:

  • BCMA (B cell maturation antigen)
  • TACI (transmembrane activator and calcium modulator and cyclophylin ligand interactor)
  • BAFF-R (also known as BR3)

These receptors are not present in early B cell precursors or in pre-B cells (stage at which CD20 receptors appear). They are present in primary mature B cells and in mature B cells (in this last stage, CD20 receptors have disappeared).

BLyS is secreted, sometimes under the influence of interferon-gamma, by a variety of cells: monocytes and macrophages, bone marrow stromal cells, astrocytes, synoviocytes during rheumatoid arthritis, salivary epithelial cells during Sjögren's syndrome, astrocytes in certain glioblastomas.

Lymphocyte apoptosis may be decreased by BLyS because stimulation of BAFF-R and BCMA increases levels of Bcl-2, which is a key anti-apoptotic mediator. Stimulation of all 3 BLyS receptors increases intranuclear levels of NF kappa B, active on differentiation and proliferation.

BLyS is not the only activator of B lymphocytes. APRIL (a proliferation activating ligand) also plays a key role[10], but is only active on BCMA and TACI.

Mechanism of action

It is possible that belimumab binds primarily to circulating soluble BLyS, therefore not inducing antibody-dependent cellular cytotoxicity that could be expected from this IgG1-type antibody. Belimumab does reduce the number of circulating B cells, but seemingly less deeply and durably than anti-CD20 monoclonal antibodies (this impression was given at the June 2007 European League against Rheumatism symposium). Only comparative trials will clarify this impression.

Other drugs addressing B lymphocyte hyperactivity

Atacicept is a recombinant fusion protein built with the extracellular ligand binding portion of TACI. It blocks activation of TACI by April and BLyS. It failed a phase II trial for Multiple sclerosis[11].

BR3-Fc is a recombinant fusion protein built with the extracellular ligand-binding portion of BAFF-R. It blocks activation of this receptor by BLyS, and is in early stage pharmaceutical development.

Anti-CD20 monoclonals: Rituximab has approved for some indications. Ocrelizumab, Ofatumumab and 3rd generation anti CD20 monoclonals are in development.

References

  1. ^ Bossen C, Schneider P (2006). "BAFF, APRIL and their receptors: structure, function and signaling". Semin. Immunol. 18 (5): 263–75. doi:10.1016/j.smim.2006.04.006. PMID 16914324. {{cite journal}}: Unknown parameter |month= ignored (help)
  2. ^ Crowley JE, Treml LS, Stadanlick JE, Carpenter E, Cancro MP (2005). "Homeostatic niche specification among naïve and activated B cells: a growing role for the BLyS family of receptors and ligands". Semin. Immunol. 17 (3): 193–9. doi:10.1016/j.smim.2005.02.001. PMID 15826824.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ http://clinicaltrials.gov/ct2/show/NCT00424476 "A Study of Belimumab in Subjects With Systemic Lupus Erythematosus (SLE) (BLISS-52)" Completed.
  4. ^ http://www.lse.co.uk/FinanceNews.asp?ArticleCode=mcjhdftaztu509y&ArticleHeadline=UPDATE_2FDA_sets_panel_for_GlaxoHuman_Genome_lupus_drug "FDA Sets Panel For Glaxo-Human Genome Lupus Drug."
  5. ^ http://clinicaltrials.gov/ct2/show/NCT00071812 "A Safety and Efficacy Study of LymphoStat-B (Monoclonal Anti-BLyS Antibody) in Subjects With Rheumatoid Arthritis (RA) "
  6. ^ Shu HB, Hu WH, Johnson H (1999). "TALL-1 is a novel member of the TNF family that is down-regulated by mitogens". J. Leukoc. Biol. 65 (5): 680–3. PMID 10331498. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Moore PA, Belvedere O, Orr A; et al. (1999). "BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator". Science. 285 (5425): 260–3. doi:10.1126/science.285.5425.260. PMID 10398604. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Edwards BM, Barash SC, Main SH; et al. (2003). "The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS". J. Mol. Biol. 334 (1): 103–18. doi:10.1016/j.jmb.2003.09.054. PMID 14596803. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Baker KP, Edwards BM, Main SH; et al. (2003). "Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator". Arthritis Rheum. 48 (11): 3253–65. doi:10.1002/art.11299. PMID 14613291. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help); Unknown parameter |unused_data= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Schneider P (2005). "The role of APRIL and BAFF in lymphocyte activation". Curr. Opin. Immunol. 17 (3): 282–9. doi:10.1016/j.coi.2005.04.005. PMID 15886118.
  11. ^ http://clinicaltrials.gov/ct2/show/NCT00642902

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