Belimumab
Encyclopedia
Belimumab is a fully human monoclonal antibody that inhibits B-lymphocyte stimulator
(BLyS), also known as B cell
activation factor of the TNF
family (BAFF). It is approved in the U.S., Canada
and Europe
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 1999. The protein was called BAFF in a paper published by Journal of Experimental medicine
in June 1999 and BLyS (or B-lymphocyte stimulator) in a paper published
by Human Genome Sciences
in July that year. BLyS plays a key role in B lymphocyte differentiation, survival and activation. Belimumab was developed in collaboration with Cambridge Antibody Technology
, where it was discovered as LymphoStat-B.
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. "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." It has subsequently been approved for use in Europe and Canada .
(SLE). 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. GlaxoSmithKline
will be the producer and marketer of the drug. It will sell for about US$35,000 per year per patient.
. Preliminary results in November 2005 were encouraging.
, diarrhea
, fever
, and infusion-site reactions. It is suggested that patients be treated with an antihistamine
prior to a belimumab infusion.
A greater number of death
s and serious infections were reported in patients treated with belimumab than in those treated with placebo
. Live vaccines should not be administered during treatment with belimumab.
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: monocyte
s and macrophage
s, bone marrow
stromal cell
s, astrocyte
s, 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, 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. Only comparative trials will clarify this impression.
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.
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". 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.
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.
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 been approved for some indications. Ocrelizumab
, ofatumumab
and third generation anti CD20 monoclonals are in development.
B-cell activating factor
B-cell activating factor also known as tumor necrosis factor ligand superfamily member 13B is a protein that in humans is encoded by the TNFLSF13B gene...
(BLyS), also known as B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
activation factor of the TNF
Tumor necrosis factors
Tumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...
family (BAFF). It is approved in the U.S., Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
and Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
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 1999. The protein was called BAFF in a paper published by Journal of Experimental medicine
Journal of Experimental Medicine
The Journal of Experimental Medicine is a peer-reviewed academic journal published by the Rockefeller University Press that publishes research papers and commentaries on the physiological, pathological, and molecular mechanisms that encompass the host response to disease...
in June 1999 and BLyS (or B-lymphocyte stimulator) in a paper published
by Human Genome Sciences
Human Genome Sciences
Human Genome Sciences is a biopharmaceutical corporation founded in 1992. It uses the human DNA sequence to develop protein and antibody drugs. As of 2008, it has drugs under development to treat such diseases as hepatitis C, systemic lupus erythmatosis, anthrax disease, cancer, rheumatoid...
in July that year. BLyS plays a key role in B lymphocyte differentiation, survival and activation. Belimumab was developed in collaboration with Cambridge Antibody Technology
Cambridge Antibody Technology
Cambridge Antibody Technology was a biotechnology company headquartered in Cambridge, United Kingdom...
, where it was discovered as LymphoStat-B.
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
Number needed to treat
The number needed to treat is an epidemiological measure used in assessing the effectiveness of a health-care intervention, typically a treatment with medication. The NNT is the average number of patients who need to be treated to prevent one additional bad outcome...
, 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. "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." It has subsequently been approved for use in Europe and Canada .
Systemic lupus erythematosus
Belimumab successfully met the primary endpoints in its phase III clinical trials for systemic lupus erythematosusSystemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
(SLE). 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. GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
will be the producer and marketer of the drug. It will sell for about US$35,000 per year per patient.
Rheumatoid arthritis
Belimumab has also undergone phase II clinical trials for rheumatoid arthritisRheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
. Preliminary results in November 2005 were encouraging.
Side effects and contraindications
Common adverse effects reported with belimumab include nauseaNausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, and infusion-site reactions. It is suggested that patients be treated with an antihistamine
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
prior to a belimumab infusion.
A greater number of death
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
s and serious infections were reported in patients treated with belimumab than in those treated with placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
. 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:- BCMATNFRSF17-Interactions:TNFRSF17 has been shown to interact with the B-cell activating factor TNFSF13B. A conserved domain at the N-terminus, BCMA TALL-1 binding domain, is required for binding to the TNFSF13B.-Further reading:...
(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
CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....
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
Interferon-gamma
Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
, by a variety of cells: monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
s and macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s, bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
stromal cell
Stromal cell
In cell biology, stromal cells are connective tissue cells of any organ, for example in the uterine mucosa , prostate, bone marrow, and the ovary. They are cells that support the function of the parenchymal cells of that organ...
s, astrocyte
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
s, synoviocytes during rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, salivary epithelial cells during Sjögren's syndrome
Sjögren's syndrome
Sjögren's syndrome , also known as "Mikulicz disease" and "Sicca syndrome", is a systemic autoimmune disease in which immune cells attack and destroy the exocrine glands that produce tears and saliva....
, astrocytes in certain glioblastomas.
Lymphocyte apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
may be decreased by BLyS because stimulation of BAFF-R and BCMA increases levels of Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
, 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, 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
Antibody-dependent cellular cytotoxicity
Antibody-Dependent Cell-Mediated Cytotoxicity is a mechanism of cell-mediated immunity whereby an effector cell of the immune system actively lyses a target cell that has been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune...
that could be expected from this IgG1
Immunoglobulin G
Immunoglobulin G are antibody molecules. Each IgG is composed of four peptide chains — two heavy chains γ and two light chains. Each IgG has two antigen binding sites. Other immunoglobulins may be described in terms of polymers with the IgG structure considered the monomer.IgG constitutes 75%...
-type antibody. Belimumab does reduce the number of circulating B cells, but seemingly less deeply and durably than anti-CD20
CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....
monoclonal antibodies. Only comparative trials will clarify this impression.
History
In 1999 a protein with immune stimulant properties was discovered and named TALL-1 and BLyS. In 2003 researchers reported that by using phage displayPhage display
Phage display is a method for the study of protein–protein, protein–peptide, and protein–DNA interactions that uses bacteriophages to connect proteins with the genetic information that encodes them. Phage Display was originally invented by George P...
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.
Belimumab was developed in early collaboration with Cambridge Antibody Technology
Cambridge Antibody Technology
Cambridge Antibody Technology was a biotechnology company headquartered in Cambridge, United Kingdom...
, 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". 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.
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.
Other drugs addressing B lymphocyte hyperactivity
AtaciceptAtacicept
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 and a proliferation-inducing ligand ,...
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
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
.
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
Rituximab
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
has been approved for some indications. Ocrelizumab
Ocrelizumab
Ocrelizumab is a humanized anti-CD20 monoclonal antibody. It targets mature B lymphocytes and hence is an immunosuppressive drug candidate. It is under development by Hoffmann–La Roche's subsidiary Genentech, and Biogen Idec....
, ofatumumab
Ofatumumab
Ofatumumab is a human monoclonal antibody which appears to inhibit early-stage B lymphocyte activation...
and third generation anti CD20 monoclonals are in development.