Belimumab

drugbox-mab


source = Recombinant
target = BLyS
CAS_number =
ATC_prefix =
ATC_suffix =
PubChem =
DrugBank =
chemical_formula =
molecular_weight =
bioavailability =
protein_bound =
metabolism =
elimination_half-life =
excretion =
pregnancy_AU =
pregnancy_US =
pregnancy_category =
legal_AU =
legal_CA =
legal_UK =
legal_US =
legal_status =
routes_of_administration =

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.

Interaction of BLyS with B lymphocytes

BLyS (also known as BAFF) plays a key role in B lymphocyte differentiation, survival and activation. [cite journal |author=Crowley JE, Treml LS, Stadanlick JE, Carpenter E, Cancro MP |title=Homeostatic niche specification among naïve and activated B cells: a growing role for the BLyS family of receptors and ligands |journal=Semin. Immunol. |volume=17 |issue=3 |pages=193–9 |year=2005 |pmid=15826824 |doi=10.1016/j.smim.2005.02.001] 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 [cite journal |author=Schneider P |title=The role of APRIL and BAFF in lymphocyte activation |journal=Curr. Opin. Immunol. |volume=17 |issue=3 |pages=282–9 |year=2005 |pmid=15886118 |doi=10.1016/j.coi.2005.04.005] , 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.Healthvalue.net. [http://www.healthvalue.net/Hyperactive_BLymphocytes_Therapies.html "Hyperactive B lymphocytes: Therapies"] Last accessed June 19, 2007.]

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.

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

References

*