Belimumab

Belimumab

Monoclonal antibody
Type	Whole antibody
Source	Template:Infobox drug/mab source
Target	B-cell activating factor
Identifiers
CAS Number	356547-88-1
ATC code	none

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).

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..

Belimumab is in phase III clinical trials for Systemic Lupus Erythematosus (SLE).

It has undergone phase II clinical trials for rheumatoid arthritis.

Discovery and development

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

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, 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.

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

pl:Belimumab