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Belimumab



Belimumab?
Therapeutic monoclonal antibody
Source Recombinant
Target BLyS
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Belimumab (registered name 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). It is being developed by Human Genome Sciences Inc. and GlaxoSmithKline. BLyS is a protein necessary for the maturation of B lymphocytes.

Additional recommended knowledge

Contents

Interaction of BLyS with B lymphocytes

BLyS (also known as BAFF) plays a key role in B lymphocyte differentiation, survival and activation.[1] 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 is decreased because stimulation of BAFF-R and BCMA increases levels of Bcl-2 (a key anti-apoptotic mediator). Stimulation of all 3 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[2], but is only active on BCMA and TACI.

Mechanism of action of belimumab

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

Diseases with B lymphocyte hyperactivity

B lymphocyte hyperactivity is known in malignant and non-malignant diseases.

Among the malignant diseases (B cell malignancies):

Among the non-malignant diseases:

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 is being developed by Zymogenetics and Serono/Merck KgaA. Early stage trials are ongoing in B cell malignancies (Multiple Myeloma), Systemic Lupus Erythematosus and Rheumatoid arthritis.[3]

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. It is in early stage development by Biogen and Genentech.[3]

Anti-CD20 monoclonals: Rituximab is approved. Ocrelizumab, Ofatumumab and 3rd generation anti CD20 monoclonals are being developed.[3]

References

  • 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.
  1. ^ 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.
  2. ^ 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.
  3. ^ a b c Healthvalue.net. "Hyperactive B lymphocytes: Therapies" Last accessed June 19, 2007.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Belimumab". A list of authors is available in Wikipedia.
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