Belimumab

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Belimumab
Belimumab 5Y9K.png
Fab fragment of belimumab. PDB: 5Y9K ​.
Monoclonal antibody
Type Whole antibody
Source Human
Target B-cell activating factor (BAFF, BLyS)
Clinical data
Trade names Benlysta
Other namesLymphoStat-B
AHFS/Drugs.com Monograph
MedlinePlus a611027
License data
Pregnancy
category
Routes of
administration 		Intravenous, subcutaneous
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C6358H9904N1728O2010S44
Molar mass 144121.90 g·mol−1
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Belimumab, sold under the brand name Benlysta, is a human monoclonal antibody that inhibits B-cell activating factor (BAFF), [6] also known as B-lymphocyte stimulator (BLyS). [7] It is approved in the United States [8] and Canada, [9] and the European Union [5] to treat systemic lupus erythematosus and lupus nephritis. [10]

Contents

The most common side effects include bacterial infections, such as bronchitis (infection in the lungs) and infection of the urinary tract (structures that produce or carry urine), diarrhea and nausea (feeling sick). [5]

Medical uses

Belimumab is indicated for the treatment of active systemic lupus erythematosus and active lupus nephritis. [4] [5]

Side effects and interactions

Common adverse effects reported with belimumab include nausea, diarrhea, and fever, as well as hypersensitivity and infusion-site reactions, which were severe in 0.9% of patients. Regulatory agencies recommend that patients be treated with an antihistamine prior to a belimumab infusion. [11]

Because belimumab is an immunosuppressant, more serious infections and deaths were reported among patients treated with the drug than among those treated with placebo. [12]

No interaction studies have been carried out, but combining belimumab with other immunosuppressants—especially those targeting B lymphocytes, such as anti-CD20 therapies—could increase the risk of severe infections. Likewise, combining belimumab with intravenous cyclophosphamide or live vaccines is not recommended. [4] [11]

Mechanism of action

Space-filling model illustrating three molecules of belimumab (tan/orange) binding a homotrimer of BAFF. PDB: 5Y9J . Belimumab 5Y9K binding BAFF homotrimer.png
Space-filling model illustrating three molecules of belimumab (tan/orange) binding a homotrimer of BAFF. PDB: 5Y9J ​.

B lymphocytes (B cells), which are part of the normal immune response, are also responsible for the over-aggressive response seen in autoimmune diseases like systemic lupus erythematosus. B cells develop in the bone marrow and continue to mature peripherally in secondary lymphoid organs and in the gut. When autoimmune B cells attack the body's own tissues, they are normally destroyed by cell suicide (apoptosis). Researchers theorize that systemic lupus erythematosus is caused when autoimmune B cells proliferate and survival factors protect them from cell suicide.[ medical citation needed ]

B-cell activating factor (BAFF), also called B-lymphocyte stimulator (BLyS), is required for the development and survival of B cells. In systemic lupus erythematosus patients, BAFF is overexpressed, which may cause autoimmune B cell proliferation and survival. Belimumab binds to BAFF and prevents it from binding to B cells. Without BAFF, B cells commit suicide and no longer contribute to the autoimmune damage of systemic lupus erythematosus.[ medical citation needed ]

BAFF is secreted by a variety of cells: monocytes and macrophages; bone marrow stromal cells; astrocytes in certain glioblastomas; synoviocytes in rheumatoid arthritis; and salivary epithelial cells in Sjögren syndrome. It interacts with three membrane receptors on B lymphocytes:[ medical citation needed ]

When BAFF binds to BAFF-R and BCMA on B cells, levels of Bcl-2, a survival factor, are increased. When all three BAFF receptors are stimulated, levels of NF kappa B, which contributes to cell proliferation and differentiation, are increased in the nucleus.[ medical citation needed ]

Another B-cell activator similar to BAFF is APRIL (A proliferation-inducing ligand), [13] but APRIL activates only BCMA and TACI, not BAFF-R.[ medical citation needed ]

Belimumab reduces the number of circulating B cells, but anti-CD20 monoclonal antibodies reduce the number even more. It is possible that belimumab binds primarily to circulating soluble BAFF and therefore does not induce the antibody-dependent cellular cytotoxicity that could be expected from this IgG1-type antibody. [14] .[ better source needed ]

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 jointly published a paper detailing their findings in May 1999 and named the protein TALL-1. [15] 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 (short for B lymphocyte stimulator). [16] Six years later, research showing the key role of BLyS in B cell differentiation, survival, and activation was published. [17]

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. [18] In 2003, CAT researchers reported that, by using phage display technology, they had elicited an array of more than 1,000 distinct antibodies, half of which inhibited binding of BLyS to its receptor. [19] Later that year, one of these antibodies was isolated and characterized. It was named LymphoStat-B and subsequently called belimumab. [20]

In August 2006, HGS and GlaxoSmithKline (GSK) entered into a co-development and commercialization agreement under which HGS would conduct Phase III trials for belimumab with assistance from GSK. The companies would share equally in Phase III/IV development costs, sales and marketing expenses, and profits of any product commercialized under the agreement. [18] On 13 February 2007, HGS and GSK announced the initiation of the first of two Phase III clinical trials of belimumab in patients with active lupus erythematosus. [21]

Two Phase III clinical studies were conducted, involving a total of 1,684 patients with scores of ≥6 on the SELENA-SLEDAI assessment of lupus activity. The primary end point was a reduction of ≥4 on the SELENA-SLEDAI assessment, and several other factors, after 52 weeks. Belimumab significantly improved the response rate, reduced disease activity and severe flares, and was well tolerated. Among patients treated with belimumab (10mg/kg) in addition to standard therapy, 58% had SELENA-SLEDAI scores reduced by ≥4 points over 52 weeks, compared with 46% of patients treated with placebo. [22] [23] However, patients of African-American or African descent did not respond significantly to belimumab. [24] [25] [26]

These trials did not include patients with the most severe forms of systemic lupus erythematosus, which involve active damage to the kidneys or central nervous system. Subjects with active kidney disease were included in Phase II trials. [27]

Clinical trials found belimumab to be safe in treating systemic lupus erythematosus, [22] [23] [28] but the magnitude of benefit was small, [8] and Phase III trials excluded the most severe cases of systemic lupus erythematosus, involving kidney and brain damage. Reviewers at the US Food and Drug Administration (FDA) expressed concern that the drug was only "marginally" effective, and that there were more deaths in the treatment group. Defenders said that in addition to its modest efficiency, belimumab allowed patients to significantly reduce their use of corticosteroids. [29]

Belimumab was not effective in Phase II clinical trials for rheumatoid arthritis. [30] It was moderately effective in Phase II trials for Sjögren syndrome. [31]

In December 2020, belimumab was approved by the FDA as a treatment for lupus nephritis in combination with standard treatment. [32]

Society and culture

Under the brand name Benlysta, belimumab received FDA approval for the treatment of systemic lupus erythematosus in March 2011, [33] despite concerns among advisory committee members that the improvement of 4 points on the SELENA-SLEDA scale was marginal, and despite reservations about additional deaths in the treatment group. [24] [34] It was subsequently approved in Canada and the European Union as well. [9] [5]

In February 2023, belimumab was given orphan drug designation by the FDA for the potential treatment of systemic sclerosis. [35] [36]

Economics

Belimumab is primarily used in people with systemic lupus erythematosus. When it was introduced in 2011, it was the first new drug approved to treat lupus in 56 years. [8] Sales rose to $31.2 million in the first quarter of 2012. [37]

The total cost for the first year of treatment with belimumab is $28,000. [38] Belimumab is much more expensive than other drugs used to treat lupus, including prednisone ($140 per year), hydroxychloroquine ($132), oral methotrexate ($432), azathioprine ($468), and mycophenolate mofetil ($1,224). [38]

In the United Kingdom, the National Institute for Health and Care Excellence calculated the cost of belimumab at £61,200 per quality-adjusted life year (QALY). This is more than the normally accepted cost of £20,000 to £30,000 per QALY. The manufacturer offered the UK National Health Service a discount of a confidential amount, which still did not bring it into the acceptable range. [39]

Research

Blisibimod, an inhibitor of both soluble and membrane-bound BAFF, has demonstrated similar reductions of B cells in clinical trials and is being investigated in a Phase II clinical study for patients with lupus.

BR3-Fc, a recombinant fusion protein built with the extracellular ligand-binding portion of BAFF-R, blocks activation of this receptor by BLyS and is in early-stage pharmaceutical development. [40]

Rituximab, an anti-CD20 monoclonal antibody, has been approved for some indications. Ocrelizumab, ofatumumab, and "third-generation" anti-CD20 monoclonals are in development.[ citation needed ]

Other drugs addressing B lymphocyte hyperactivity include atacicept, a recombinant fusion protein that is built with the extracellular ligand binding portion of TACI and blocks activation of TACI by APRIL and BLyS. It failed a Phase II trial for multiple sclerosis. [41] [42]

Related Research Articles

<span class="mw-page-title-main">Immunosuppressive drug</span> Drug that inhibits activity of immune system

Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.

<span class="mw-page-title-main">Rituximab</span> Biopharmaceutical drug

Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow intravenous infusion. Biosimilars of Rituxan include Blitzima, Riabni, Ritemvia, Rituenza, Rixathon, Ruxience, and Truxima.

<span class="mw-page-title-main">Human Genome Sciences</span> Former American pharmaceutical company, acquired by GlaxoSmithKline.

Human Genome Sciences (HGS) was a biopharmaceutical corporation founded in 1992 by Craig Venter, Alan Walton and Wally Steinberg. It uses the human DNA sequence to develop protein and antibody drugs. It had drugs under development to treat such diseases as hepatitis C, systemic lupus erythmatosis, anthrax, and cancer. It collaborated with other biotechnology and pharmaceutical companies for development partnerships and licensing.

<span class="mw-page-title-main">Biological therapy for inflammatory bowel disease</span>

Biological therapy, the use of medications called biopharmaceuticals or biologics that are tailored to specifically target an immune or genetic mediator of disease, plays a major role in the treatment of inflammatory bowel disease. Even for diseases of unknown cause, molecules that are involved in the disease process have been identified, and can be targeted for biological therapy. Many of these molecules, which are mainly cytokines, are directly involved in the immune system. Biological therapy has found a niche in the management of cancer, autoimmune diseases, and diseases of unknown cause that result in symptoms due to immune related mechanisms.

Ocrelizumab, sold under the brand name Ocrevus, is a medication used for the treatment of multiple sclerosis (MS). It is a humanized anti-CD20 monoclonal antibody. It targets CD20 marker on B lymphocytes and is an immunosuppressive drug. Ocrelizumab binds to an epitope that overlaps with the epitope to which rituximab binds.

<span class="mw-page-title-main">CD22</span> Lectin molecule

CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule that prevents the overactivation of the immune system and the development of autoimmune diseases.

<span class="mw-page-title-main">Ofatumumab</span> Medication

Ofatumumab is a fully human monoclonal antibody to CD20, which appears to provide rapid B-cell depletion. Under the brand name Kesimpta, it is approved for the treatment of multiple sclerosis in the United States as well as in the European Union and other regions. Under the brand name Arzerra, it is approved for the treatment of certain types of chronic lymphocytic leukemia (CLL) in the United States. It is sold by Novartis under license from Genmab.

<span class="mw-page-title-main">B-cell activating factor</span> Mammalian protein found in Homo sapiens

B-cell activating factor (BAFF) also known as tumor necrosis factor ligand superfamily member 13B and CD257 among other names, is a protein that in humans is encoded by the TNFSF13B gene. BAFF is also known as B Lymphocyte Stimulator (BLyS) and TNF- and APOL-related leukocyte expressed ligand (TALL-1) and the Dendritic cell-derived TNF-like molecule.

<span class="mw-page-title-main">Interferon alpha-1</span> Protein-coding gene in the species Homo sapiens

Interferon alpha-1 is a protein that in humans is encoded by the IFNA1 gene.

<span class="mw-page-title-main">B-cell maturation antigen</span> Protein-coding gene in the species Homo sapiens

B-cell maturation antigen, also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17), is a protein that in humans is encoded by the TNFRSF17 gene.

<span class="mw-page-title-main">Lupus</span> Human autoimmune disease

Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common symptoms include painful and swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes, feeling tired, and a red rash which is most commonly on the face. Often there are periods of illness, called flares, and periods of remission during which there are few symptoms.

Atacicept is a recombinant fusion protein designed to inhibit B cells, thereby suppressing autoimmune disease. The designer protein combines the binding site for two cytokines that regulate maturation, function, and survival of B cells - B-lymphocyte stimulator (BLyS) and A proliferation-inducing ligand (APRIL), with the constant region of immunoglobin. Atacicept blocks activation of B cells by the tumor necrosis factor receptor superfamily member 13B, a transmembrane receptor protein found predominantly on the surface of B cells. Like the monoclonal antibody belimumab, atacicept blocks the binding of BLyS, but it also blocks APRIL. Binding of these TACI ligands induces proliferation, activation, and longevity of B cells and thus their production of autoantibodies. Atacicept is thought to selectively impair mature B cells and plasma cells with less impact on progenitor cells and memory B cells.

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<span class="mw-page-title-main">Anthera Pharmaceuticals</span> American biopharmaceutical company

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Ixekizumab, sold under the brand name Taltz, is an injectable medication for the treatment of autoimmune diseases. Chemically, it is a form of a humanized monoclonal antibody. The substance acts by binding interleukin 17A and neutralizing it, reducing inflammation.

Tabalumab is an anti-B-cell activating factor (BAFF) human monoclonal antibody designed for the treatment of autoimmune diseases and B cell malignancies. Tabalumab was developed by Eli Lilly and Company.

<span class="mw-page-title-main">Voclosporin</span> Chemical compound

Voclosporin, sold under the brand name Lupkynis, is a calcineurin inhibitor used as an immunosuppressant medication for the treatment of lupus nephritis. It is an analog of ciclosporin that has enhanced action against calcineurin and greater metabolic stability.

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Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody used as an anti-cancer medication for the treatment of endometrial cancer. Dostarlimab is a programmed death receptor-1 (PD-1)–blocking monoclonal antibody.

Ianalumab is a monoclonal antibody that is being investigated for autoimmune hepatitis, multiple sclerosis, pemphigus vulgaris, rheumatoid arthritis, Sjögren syndrome, and systemic lupus erythematosus.

References

  1. ↑ "Belimumab (Benlysta) Use During Pregnancy". Drugs.com. 5 February 2020. Archived from the original on 4 December 2020. Retrieved 29 July 2020.
  2. ↑ "BENLYSTA (GlaxoSmithKline Australia Pty Ltd)". Therapeutic Goods Administration (TGA). 11 November 2022. Retrieved 15 April 2023.
  3. ↑ "Benlysta Product information". Health Canada. 22 October 2009. Retrieved 17 March 2023.
  4. 1 2 3 "Benlysta- belimumab injection, powder, lyophilized, for solution Benlysta- belimumab solution". DailyMed. 17 January 2020. Archived from the original on 25 September 2020. Retrieved 29 July 2020.
  5. 1 2 3 4 5 "Benlysta EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 25 October 2020. Retrieved 29 July 2020.
  6. ↑ Bossen C, Schneider P (October 2006). "BAFF, APRIL and their receptors: structure, function and signaling" (PDF). Seminars in Immunology. 18 (5): 263–275. doi:10.1016/j.smim.2006.04.006. PMID   16914324.
  7. ↑ Kaveri SV, Mouthon L, Bayry J (September 2010). "Basophils and nephritis in lupus". The New England Journal of Medicine. 363 (11): 1080–1082. doi:10.1056/NEJMcibr1006936. PMID   20825323.
  8. 1 2 3 Belimumab: The first drug to be FDA approved for the treatment of lupus since 1955 Archived 13 September 2021 at the Wayback Machine , By Rebecca Manno, Johns Hopkins Arthritis Center, 15 July 2011
  9. 1 2 DrugBank DB08879
  10. ↑ "Benlysta now approved in Canada in addition to standard therapy for treatment of active lupus nephritis in adult patients" (Press release). GlaxoSmithKline. 30 July 2021. Retrieved 17 March 2023– via Newswire.
  11. 1 2 European Medicines Agency: Benlysta Summary of Product Characteristics Archived 18 June 2018 at the Wayback Machine
  12. ↑ "GlaxoSmithKline and Human Genome Sciences announce FDA approval of Benlysta (belimumab) for the treatment of systemic lupus erythematosus". GlaxoSmithKline. 9 March 2011. Archived from the original on 17 March 2011. Retrieved 11 March 2011.
  13. ↑ Schneider P (June 2005). "The role of APRIL and BAFF in lymphocyte activation". Current Opinion in Immunology. 17 (3): 282–289. doi:10.1016/j.coi.2005.04.005. PMID   15886118.
  14. ↑ June 2007 European League against Rheumatism symposium.
  15. ↑ Shu HB, Hu WH, Johnson H (May 1999). "TALL-1 is a novel member of the TNF family that is down-regulated by mitogens". Journal of Leukocyte Biology. 65 (5): 680–683. doi: 10.1002/jlb.65.5.680 . PMID   10331498. S2CID   1498303.
  16. ↑ Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, et al. (July 1999). "BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator". Science. 285 (5425): 260–263. doi:10.1126/science.285.5425.260. PMID   10398604.
  17. ↑ Crowley JE, Treml LS, Stadanlick JE, Carpenter E, Cancro MP (June 2005). "Homeostatic niche specification among naïve and activated B cells: a growing role for the BLyS family of receptors and ligands". Seminars in Immunology. 17 (3): 193–199. doi:10.1016/j.smim.2005.02.001. PMID   15826824.
  18. 1 2 "Benlysta (belimumab)". Human Genome Sciences. Archived from the original on 21 April 2011. Retrieved 11 March 2011.
  19. ↑ Edwards BM, Barash SC, Main SH, Choi GH, Minter R, Ullrich S, et al. (November 2003). "The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS". Journal of Molecular Biology. 334 (1): 103–118. doi:10.1016/j.jmb.2003.09.054. PMID   14596803.
  20. ↑ Baker KP, Edwards BM, Main SH, Choi GH, Wager RE, Halpern WG, et al. (November 2003). "Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator". Arthritis and Rheumatism. 48 (11): 3253–3265. doi:10.1002/art.11299. PMID   14613291.
  21. ↑ "Human Genome Sciences And Glaxosmithkline Announce Initiation Of Phase 3 Clinical Trial Of Lymphostat-B In Systemic Lupus Erythematosus" (Press release). Human Genome Sciences. 13 February 2007. Archived from the original on 25 April 2011. Retrieved 11 March 2011.
  22. 1 2 Navarra SV, Guzmán RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, et al. (BLISS-52 Study Group) (February 2011). "Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial". Lancet. 377 (9767): 721–731. doi:10.1016/S0140-6736(10)61354-2. PMID   21296403. S2CID   28952240. Archived from the original on 17 October 2012. Retrieved 31 October 2012.
  23. 1 2 Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzová D, et al. (BLISS-76 Study Group) (December 2011). "A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus". Arthritis and Rheumatism. 63 (12): 3918–3930. doi:10.1002/art.30613. PMC   5007058 . PMID   22127708.
  24. 1 2 FDA Questions Safety, Efficacy of Belimumab Archived 3 March 2021 at the Wayback Machine , By Emily P. Walker, Washington Correspondent, MedPage Today, 12 November 2010
  25. ↑ Summary Minutes of the Arthritis Advisory Committee Meeting November 16, 2010 Archived 4 March 2017 at the Wayback Machine U.S. Food and Drug Administration (FDA)
  26. ↑ 2010 Meeting Materials, Arthritis Advisory Committee Archived 29 March 2012 at the Wayback Machine U.S. Food and Drug Administration (FDA)
  27. ↑ Andrew Pollack, "F.D.A. Approves Benlysta, a New Lupus Drug" Archived 12 November 2020 at the Wayback Machine , The New York Times, 9 March 2011
  28. ↑ Lee YH, Song GG (January 2018). "Comparative efficacy and safety of intravenous or subcutaneous belimumab in combination with standard therapy in patients with active systemic lupus erythematosus: a Bayesian network meta-analysis of randomized controlled trials". Lupus. 27 (1): 112–119. doi: 10.1177/0961203317713143 . PMID   28592201. S2CID   26026994.
  29. ↑ "Should Belimumab Have Been Approved? Stephen Paget, Medscape Rheumatology, Mar 24, 2011". Archived from the original on 16 November 2015. Retrieved 27 April 2013.
  30. ↑ Clinical trial number NCT00071812 for "A Safety and Efficacy Study of LymphoStat-B (Monoclonal Anti-BLyS Antibody) in Subjects With Rheumatoid Arthritis" at ClinicalTrials.gov.
  31. ↑ "Efficacy and Safety of Belimumab in Subjects With Primary Sjögren's Syndrome (BELISS)". July 2012. Archived from the original on 18 October 2012. Retrieved 1 November 2012.
  32. ↑ "FDA Approves Belimumab & Voclosporin for Lupus Nephritis". The Rheumatologist. 24 March 2021. Archived from the original on 5 May 2021. Retrieved 3 May 2021.
  33. ↑ "FDA approves Benlysta to treat lupus" (Press release). U.S. Food and Drug Administration (FDA). 9 March 2011. Archived from the original on 11 March 2011.
  34. ↑ Pollack A (16 November 2010). "Benlysta, Lupus Treatment, Endorsed by F.D.A." The New York Times . Archived from the original on 9 November 2020. Retrieved 29 July 2020.
  35. ↑ "Benlysta granted Orphan Drug Designation by US FDA for the potential treatment of systemic sclerosis". GSK (Press release). Archived from the original on 9 February 2023. Retrieved 9 February 2023.
  36. ↑ "GSK Says Benlysta Granted Orphan Drug Designation By FDA". MarketScreener. February 2023. Archived from the original on 9 February 2023. Retrieved 9 February 2023.
  37. ↑ HGSI Cuts Loss on Benlysta Sales Archived 7 April 2019 at the Wayback Machine , By Zacks Equity Research, 26 April 2012
  38. 1 2 Hahn BH (April 2013). "Belimumab for systemic lupus erythematosus". The New England Journal of Medicine. 368 (16): 1528–1535. doi:10.1056/NEJMct1207259. PMID   23594005.
  39. ↑ NICE publishes draft guidance on belimumab for systemic lupus erythematosus Archived 12 September 2012 at the Wayback Machine , press release, 26 April 2012
  40. ↑ Vugmeyster Y, Seshasayee D, Chang W, Storn A, Howell K, Sa S, et al. (February 2006). "A soluble BAFF antagonist, BR3-Fc, decreases peripheral blood B cells and lymphoid tissue marginal zone and follicular B cells in cynomolgus monkeys". The American Journal of Pathology. 168 (2): 476–489. doi:10.2353/ajpath.2006.050600. PMC   1606502 . PMID   16436662.
  41. ↑ Clinical trial number NCT00642902 for "Atacicept in Multiple Sclerosis, Phase II" at ClinicalTrials.gov
  42. ↑ Kappos L, Hartung HP, Freedman MS, Boyko A, Radü EW, Mikol DD, et al. (ATAMS Study Group) (April 2014). "Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial". The Lancet. Neurology. 13 (4): 353–363. doi:10.1016/S1474-4422(14)70028-6. PMID   24613349. S2CID   38926361.
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