Belimumab

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

What is the Correct Way to Check Repeatability in Balances?

Don't let static charges disrupt your weighing accuracy

How to ensure accurate weighing results every day?

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):

• non-Hodgkin lymphoma
• chronic lymphocytic leukemia
• multiple myeloma

Among the non-malignant diseases:

• Multiple sclerosis
• Rheumatoid arthritis
• Systemic lupus erythematosus - It is in this last field that Belimumab is the most advanced (2 phase 3 trials ongoing, with regulatory filing possibly in 2010).

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.