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Belimumab

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Belimumab
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetB-cell activating factor
Clinical data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
KEGG
Chemical and physical data
FormulaC6714H10428O2102S52
Molar mass151.8 kDa g·mol−1
 ☒NcheckY (what is this?)  (verify)

Belimumab (trade name Benlysta, previously known as LymphoStat-B), is a fully human monoclonal antibody that inhibits B-lymphocyte stimulator (BLyS), also known as B cell activation factor of the TNF family (BAFF).[1] It is approved in the U.S. for treatment of systemic lupus erythmatosis (SLE), and is under investigation for use in other autoimmune diseases.

TALL-1 is a naturally occurring protein that was discovered by researchers from the National Jewish Medical and Research Center and the University of Colorado who published a paper on it in May of 1999. The protein was called BLyS (or B-lymphocyte stimulator) in a paper published by Human Genome Sciences in July 1999.[2] BLyS plays a key role in B lymphocyte differentiation, survival and activation.[3] Belimumab was developed in collaboration with Cambridge Antibody Technology, where it was discovered as LymphoStat-B.[4]

Benlysta was approved by the U.S. Food and Drug Administration (FDA) for treatment of SLE on March 9, 2011. The FDA Advisory committee approved it by a 13-to-2 vote, despite reservations that the drug was only marginally effective. Based on number needed to treat, about 11 patients must be treated for one to benefit. It was not tested in severe forms of SLE, involving active damage to the kidneys or central nervous system.[5] "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." [6][7]

Uses

Systemic lupus erythematosus

Belimumab successfully met the primary endpoints in its phase III clinical trials for systemic lupus erythematosus (SLE).[8] Benlysta was the first new drug to treat lupus after 56 years. Industry analysts expect the drug to be a blockbuster, with annual sales exceeding $2.2 billion by 2014.[9][10] GlaxoSmithKline will be the producer and marketer of the drug. It will sell for about $35K per year per patient.

Rheumatoid arthritis

Belimumab has also undergone phase II clinical trials for rheumatoid arthritis.[11] Preliminary results in November 2005 were encouraging.[12]

Side effects and contraindications

Common adverse effects reported with belimumab include nausea, diarrhea, fever, and infusion-site reactions. It is suggested[who?] that patients be treated with an antihistamine prior to a belimumab infusion.

A greater number of deaths and serious infections were reported in patients treated with belimumab than in those treated with placebo.[13] Live vaccines should not be administered during treatment with belimumab.

Mechanism of action

Three membrane receptors are involved in the interaction of BLyS with B lymphocytes:

  • 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-inducing ligand) also plays a key role,[14] but is only active on BCMA and TACI.

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.[15] Only comparative trials will clarify this impression.

History

In 1999 a protein with immune stimulant properties was discovered and named TALL-1[16] and BLyS.[17] 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.[18] Later that year, human monoclonal antibody LymphoStat-B, subsequently called belimumab.[19]

Belimumab was developed in early collaboration with Cambridge Antibody Technology, where it was discovered as LymphoStat-B. On the 30 October 2000 "Human Genome Sciences and Cambridge Antibody Technology Commit to Exclusive Development of Anti-BLyS Antibodies".[4] Under this agreement, CAT would identify many clones and HGS would select appropriate ones to take into clinical trials.

In August 2006, HGS and GSK entered into a co-development and commercialization agreement under which HGS would conduct BENLYSTA Phase 3 trials, 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.[20]

On February 13, 2007 – HGSI and GSK announced the initiation of dosing in BLISS-76, one of two pivotal Phase 3 clinical trials of LymphoStat-B® (belimumab) in patients with active SLE.[21]

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.[22]

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 third generation anti CD20 monoclonals are in development.

References

  1. ^ 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. {{cite journal}}: Unknown parameter |month= ignored (help)
  2. ^ BLyS: member of the tumor necrosis factor family and B-lymphocyte stimulator. Moore PA, Belvedere O, Orr A, et al. Science. July 1999; 285: 260-263.
  3. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ a b "BENLYSTA® (belimumab) - HGS". Hgsi.com. Retrieved 2011-03-11.
  5. ^ F.D.A. Approves Benlysta, a New Lupus Drug, By ANDREW POLLACK, New York Times, March 9, 2011
  6. ^ [1]
  7. ^ http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisDrugsAdvisoryCommittee/UCM241199.pdf
  8. ^ http://clinicaltrials.gov/ct2/show/NCT00424476 "A Study of Belimumab in Subjects With Systemic Lupus Erythematosus (SLE) (BLISS-52)" ClinicalTrials.gov Identifier: NCT00424476.
  9. ^ "FDA Sets Panel For Glaxo-Human Genome Lupus Drug."
  10. ^ "FDA approves first new drug for lupus in 56 years - USATODAY.com". Yourlife.usatoday.com. Retrieved 2011-03-11.
  11. ^ http://clinicaltrials.gov/ct2/show/NCT00071812 "A Safety and Efficacy Study of LymphoStat-B (Monoclonal Anti-BLyS Antibody) in Subjects With Rheumatoid Arthritis (RA) "
  12. ^ "HUMAN GENOME SCIENCES REPORTS PHASE 2 RESULTS FOR LYMPHOSTAT-B (BELIMUMAB) IN PATIENTS WITH RHEUMATOID ARTHRITIS". 17 Nov 2005.
  13. ^ "GlaxoSmithKline and Human Genome Sciences announce FDA approval of Benlysta® (belimumab) for the treatment of systemic lupus erythematosus". GlaxoSmithKline. Retrieved 11 Mars 2011. {{cite web}}: Check date values in: |accessdate= (help); Unknown parameter |data= ignored (|date= suggested) (help)
  14. ^ 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.
  15. ^ This impression was given at the June 2007 European League against Rheumatism symposium.
  16. ^ Shu HB, Hu WH, Johnson H (1999). "TALL-1 is a novel member of the TNF family that is down-regulated by mitogens". J. Leukoc. Biol. 65 (5): 680–3. PMID 10331498. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ Moore PA, Belvedere O, Orr A; et al. (1999). "BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator". Science. 285 (5425): 260–3. doi:10.1126/science.285.5425.260. PMID 10398604. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ Edwards BM, Barash SC, Main SH; et al. (2003). "The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS". J. Mol. Biol. 334 (1): 103–18. doi:10.1016/j.jmb.2003.09.054. PMID 14596803. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ Baker KP, Edwards BM, Main SH; et al. (2003). "Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator". Arthritis Rheum. 48 (11): 3253–65. doi:10.1002/art.11299. PMID 14613291. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  20. ^ "BENLYSTA® (belimumab) - HGS". Hgsi.com. Retrieved 2011-03-11.
  21. ^ [http://www.hgsi.com/latest/human-genome-sciences-and-glaxosmithkline-announce-initiation-of-phase-3-clinical-trial-of-lymphostat-b-reg-in-systemic-lupus-erythema-2.html "HUMAN GENOME SCIENCES AND GLAXOSMITHKLINE ANNOUNCE INITIATION OF PHASE 3 CLINICAL TRIAL OF LYMPHOSTAT-B� IN SYSTEMIC LUPUS ERYTHEMATOSUS - HGS"]. Hgsi.com. 2007-02-13. Retrieved 2011-03-11. {{cite web}}: replacement character in |title= at position 104 (help)
  22. ^ Clinical trails website
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