Belimumab

Belimumab ^?

Monoclonal antibody
Type	Whole antibody
Source	Human
Target	B-cell activating factor (BAFF, BLyS)
Clinical data
Trade names	Benlysta
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a611027
Licence data	US FDA:link
Pregnancy cat.	C (US)
Legal status	℞-only (US)
Routes	Intravenous
Identifiers
CAS number	356547-88-1 N
ATC code	L04AA26
UNII	73B0K5S26A Y
KEGG	D03068 N
Chemical data
Formula	C6714H10428O2102S52
Mol. mass	151.8 kDa
N (what is this?)  (verify)

Belimumab (trade name Benlysta, previously known as LymphoStat-B) is a human monoclonal antibody that inhibits B-cell activating factor (BAFF).^[1] It is approved in the United States, Canada and Europe for treatment of systemic lupus erythematosus (SLE), and is being tested for use in other autoimmune diseases.

Uses

Systemic lupus erythematosus

Benlysta was the first new drug to treat lupus after 56 years. Industry analysts expect the drug to be a blockbuster, with annual sales forecast to exceed $2.2 billion by 2014.^[2][3] It is marketed by GlaxoSmithKline and sold for about US$35,000 per year per patient.

Rheumatoid arthritis

Belimumab has also undergone phase II clinical trials for rheumatoid arthritis.^[4] Preliminary results in November 2005 were encouraging,^[5] but no clinical trials are ongoing as of April 2012^[update].

Side effects

Common adverse effects reported with belimumab include nausea, diarrhea, fever, as well as hypersensitivity and infusion-site reactions (severe in 0.9% of patients). It is suggested that patients be treated with an antihistamine prior to a belimumab infusion.^[6]

A greater number of serious infections and deaths were reported in patients treated with belimumab than in those treated with placebo. Infections are due to the immunosuppressant properties of the drug.^[7]

Interactions

No interaction studies have been carried out. Combination of belimumab with other immunosuppressants, especially those targeting B lymphocytes such as anti-CD20 therapies, could increase the risk of severe infections. Likewise, the combination with cyclophosphamide is not recommended, as well as administering live vaccines during treatment with belimumab.^[6][8]

Mechanism of action

B-cell activating factor (BAFF) 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.

Three membrane receptors on B lymphocytes (B cells) are involved in their interaction with BAFF:

• BCMA (B cell maturation antigen)
• TACI (transmembrane activator and calcium modulator and cyclophylin ligand interactor)
• BAFF-R (BAFF receptor)

These receptors are not present in early B cell precursors or in pre-B cells (the stage at which CD20 receptors appear), but are found on primary mature B cells and in plasma B cells. In this last stage, CD20 receptors have disappeared.

Stimulation of BAFF-R and BCMA on B cells increases levels of Bcl-2, which is a key mediator for inhibiting apoptosis (cell death). Stimulation of all three BAFF receptors increases intranuclear levels of NF kappa B, active on cell proliferation and differentiation.

BAFF is not the only activator of B lymphocytes. APRIL (a proliferation-inducing ligand) also plays a key role,^[9] but only activates BCMA and TACI, not BAFF-R.

It is possible that belimumab binds primarily to circulating soluble BAFF, 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.^[10] Only comparative trials will clarify this impression.

History

B-cell activating factor is a naturally occurring protein that was discovered by researchers from National Jewish Health (previously the National Jewish Medical and Research Center) and the University of Colorado, who collaboratively published a paper detailing their findings in May 1999, naming the protein TALL-1.^[11] The same protein was named BAFF in another paper published in June 1999; and in a paper published in July of that year, Human Genome Sciences (HGS) referred to it as BLyS (or B lymphocyte stimulator).^[12] Six years later, the key role of BLyS in B cell differentiation, survival and activation was published.^[13]

Five years prior, in October 2000, HGS and Cambridge Antibody Technology (CAT) agreed to co-develop monoclonal antibodies targeted at BLyS. Under this agreement, CAT would identify antibodies and HGS would select appropriate ones to take into clinical trials.^[14] In 2003, CAT researchers reported that, by using phage display technology, they had elicited an array of over 1000 distinct antibodies, half of which inhibited binding of BLyS to its receptor.^[15] Later that year, one of these antibodies was isolated and characterized. It was named LymphoStat-B and subsequently called belimumab.^[16]

In August 2006, HGS and GlaxoSmithKline (GSK) entered into a co-development and commercialization agreement under which HGS would conduct Phase 3 trials for belimumab with assistance from GSK. The companies would share equally in Phase 3/4 development costs, sales and marketing expenses, and profits of any product commercialized under the agreement.^[14] On February 13, 2007, HGS and GSK announced the initiation of the first of two pivotal Phase 3 clinical trial of belimumab in patients with active lupus erythematosus.^[17]

Under its trade name Benlysta, belimumab was approved by the U.S. Food and Drug Administration (FDA) for treatment of SLE on March 9, 2011.^[18] The FDA Advisory committee approved it with a 13-to-2 vote, despite reservations that the drug was only marginally effective. Based on the number needed to treat, approximately eleven patients must be treated for one to benefit. It was not tested in severe forms of SLE, which involve active damage to the kidneys or central nervous system.^[19] "Patients with active lupus that involved the kidneys ... were excluded from participating in the trials. Study participants of African American or African descent did not significantly respond to belimumab." ^[20][21][22] It has subsequently been approved for use in Europe and Canada.^[23]

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.^[24]

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.^[25]

Of anti-CD20 monoclonal antibodies, rituximab has been approved for some indications. Ocrelizumab, ofatumumab and "third generation" anti-CD20 monoclonals are in development.

References