The Full Wiki

Belimumab: Wikis

Advertisements
  

Note: Many of our articles have direct quotes from sources you can cite, within the Wikipedia article! This article doesn't yet, but we're working on it! See more info or our list of citable articles.

Encyclopedia

From Wikipedia, the free encyclopedia

Belimumab ?
Monoclonal antibody
Source Recombinant
Target B-cell activating factor
Identifiers
CAS number 356547-88-1
ATC code none
PubChem  ?
Chemical data
Formula  ?
Mol. mass  ?
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes  ?

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].

Contents

Discovery and development

In 1999 protein with immune stimulant properties was called TALL-1[3] and BLyS.[4] 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.[5] Later that year, human monoclonal antibody LymphoStat-B, subsequently called belimumab.[6]

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[7], 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.

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 (October 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.  
  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.  
  3. ^ Shu HB, Hu WH, Johnson H (May 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. http://www.jleukbio.org/cgi/pmidlookup?view=long&pmid=10331498.  
  4. ^ Moore PA, Belvedere O, Orr A, et al. (July 1999). "BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator". Science 285 (5425): 260–3. PMID 10398604. http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=10398604.  
  5. ^ Edwards BM, Barash SC, Main SH, et al. (November 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. PMID 14596803. http://linkinghub.elsevier.com/retrieve/pii/S0022283603012026.  
  6. ^ Baker KP, Edwards BM, Main SH, et al. (November 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. http://dx.doi.org/10.1002/art.11299.  
  7. ^ 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.  
Advertisements

Advertisements






Got something to say? Make a comment.
Your name
Your email address
Message