Eculizumab
Encyclopedia
Eculizumab is a monoclonal antibody directed against the complement
protein C5
. Eculizumab has been shown to be effective in treating paroxysmal nocturnal hemoglobinuria (PNH)
, a rare and sometimes life threatening disease of the blood, and is approved for this indication.
Eculizumab is a recombinant
humanized monoclonal IgG2/4 antibody that specifically binds to the complement protein C5, inhibiting its cleavage by the C5 convertase which prevents the generation of the terminal complement complex C5b-9. It is this terminal complement complex that causes intravascular hemolysis
in people with (PNH).
Eculizumab is a product of Alexion Pharmaceuticals
and was approved by the United States
Food and Drug Administration
(FDA) on March 16, 2007 and the European Medicines Agency
on June 20, 2007.
According to Forbes magazine, Soliris, at $409,500 a year, is the world's single most expensive drug.
. It contains a human IgG4 heavy chain at constant regions 2 and 3 which eliminates complement activation, a human IgG4 heavy chain at constant region 1 and hinge that eliminates Fc receptor
binding and human framework regions and complementary determining regions of murine origin.
Eculizumab binds to the complement protein C5 inhibiting its cleavage to C5a and C5b which then prevents the formation of the membrane attack complex (MAC), C5b-9. This, in turn, inhibits the terminal complement-mediated intravascular hemolysis
in PNH patients. The proximal functions of complement remain intact, such as immune complex clearance (upstream from C5 in the complement sequence), microbial opsonization, and weak anaphylatoxin
function.
The mechanism of action of eculizumab in PNH can be understood by examining the cell membrane and attached proteins. The underlying defect in PNH is in a gene called PIG-A, which codes for an enzyme, phosphatidylinositol glycan A (PIG-A)
, that is necessary to form glycosylphosphatidylinositol (GPI) glycolipid, which anchors membrane proteins to the cell surface. Several proteins are normally linked to the GPI anchors on the cell membrane, including proteins that protect the cell membrane from complement-mediated destruction. When a GPI deficit exists, as occurs in PNH, complement can more easily target and lyse the deficient cells. In red blood cells, this results in cell breakdown or hemolysis. The main complement protecting proteins are CD55 which disrupts the formation of CD3 convertase, and CD59
, which binds the membrane attack complex and prevents C-9
from binding to the cell, and inducing cell breakdown. Eculizumab targets C5 and thus inhibits the complement system from destroying the otherwise vulnerable CD55 and CD59 deficient blood cells of PNH patients, producing a rapid and substantial reduction in hemolysis in almost all treated patients.
Significantly, data from three independent parent clinical studies (Phase II pilot study, Phase III TRIUMPH study, and Phase III SHEPHERD study) demonstrated a greater than 90% reduction in thromboembolic events, the most serious complication and major cause of death in PNH. All PNH patients in clinical trials showed a benefit from eculizumab therapy – many benefits occurred rapidly; others showed improvement over time.
There are also reports of eculizumab being used to treat cold agglutinin disease. In one patient cast report, eculizumab led to a sustained reduction of hemolysis, disappearance of further exacerbations, complete elimination of transfusion requirements and improvement of symptoms and quality of life.
Early results from a Mayo Clinic research study demonstrate the effectiveness of a new approach to blocking an important part of the immune system that causes severe damage to some kidney transplants
. Results show that eculizumab prevents antibody-mediated kidney transplant rejection by inhibiting the immune system's activation of one of the body's important defense mechanisms — the complement system
.
Eculizumab is well tolerated, with headache the most common adverse event on initiation of treatment.
It is administered by intravenous infusion over 35 minutes. Patients are followed and monitored for response with LDH
(measure of intravascular hemolysis), hemoglobin level (transfusion requirement), infection monitoring, and thromboembolism incidence.
activation and therefore makes patients vulnerable to infection with encapsulated organisms. Serious meningococcus infections have been described in patients who received eculizumab. Due to the increased risk of meningococcal infections, meningococcal vaccination
is recommended at least 2 weeks prior to receiving eculizumab. There is concern, however, that current meningococcal vaccines may not be sufficient to protect patients, since commonly available vaccines do not protect against strains of meningococcus with a serogroup B antigen, which is prevalent in countries such as the Netherlands.
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
protein C5
Complement component 5
Complement component 5 is a protein that in humans is encoded by the C5 gene.Complement component 5 is involved in the complement system. It is cleaved into C5a and C5b:* C5a plays an important role in chemotaxis....
. Eculizumab has been shown to be effective in treating paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria , sometimes referred to as Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood characterised by complement-induced intravascular hemolytic anemia , red urine and thrombosis...
, a rare and sometimes life threatening disease of the blood, and is approved for this indication.
Eculizumab is a recombinant
Recombinant
Recombinant may refer to:* A recombinant organism - an organism that contains a different combination of alleles from either of its parents.* Recombinant DNA - a form of artificial DNA* Recombinant virus - a virus formed by recombining genetic material...
humanized monoclonal IgG2/4 antibody that specifically binds to the complement protein C5, inhibiting its cleavage by the C5 convertase which prevents the generation of the terminal complement complex C5b-9. It is this terminal complement complex that causes intravascular hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
in people with (PNH).
Eculizumab is a product of Alexion Pharmaceuticals
Alexion Pharmaceuticals
Alexion Pharmaceuticals is the original developer and distributor of Soliris, a drug used in treating the ultra-rare disorders Hemolytic-uremic syndrome and Paroxysmal nocturnal hemoglobinuria . In a recent study Soliris was noted for its effectiveness in altering the natural course of PNH...
and was approved by the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) on March 16, 2007 and the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
on June 20, 2007.
According to Forbes magazine, Soliris, at $409,500 a year, is the world's single most expensive drug.
Biochemistry
Eculizumab is a humanized monoclonal antibody against C5CD5 (protein)
CD5 is a cluster of differentiation found on a subset of IgM-secreting B cells called B-1 cells, and also on T cells. B-1 cells have limited diversity of their B-cell receptor due to their lack of the enzyme terminal deoxynucleotidyl transferase and are potentially self-reactive...
. It contains a human IgG4 heavy chain at constant regions 2 and 3 which eliminates complement activation, a human IgG4 heavy chain at constant region 1 and hinge that eliminates Fc receptor
Fc receptor
An Fc receptor is a protein found on the surface of certain cells - including natural killer cells, macrophages, neutrophils, and mast cells - that contribute to the protective functions of the immune system....
binding and human framework regions and complementary determining regions of murine origin.
Eculizumab binds to the complement protein C5 inhibiting its cleavage to C5a and C5b which then prevents the formation of the membrane attack complex (MAC), C5b-9. This, in turn, inhibits the terminal complement-mediated intravascular hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
in PNH patients. The proximal functions of complement remain intact, such as immune complex clearance (upstream from C5 in the complement sequence), microbial opsonization, and weak anaphylatoxin
Anaphylatoxin
Anaphylatoxins, or anaphylotoxins, are fragments that are produced as part of the activation of the complement system.. Complement components C3, C4 and C5 are large glycoproteins that have important functions in the immune response and host defense...
function.
The mechanism of action of eculizumab in PNH can be understood by examining the cell membrane and attached proteins. The underlying defect in PNH is in a gene called PIG-A, which codes for an enzyme, phosphatidylinositol glycan A (PIG-A)
PIGA
Phosphatidylinositol N-acetylglucosaminyltransferase subunit A is an enzyme that in humans is encoded by the PIGA gene.-Further reading:...
, that is necessary to form glycosylphosphatidylinositol (GPI) glycolipid, which anchors membrane proteins to the cell surface. Several proteins are normally linked to the GPI anchors on the cell membrane, including proteins that protect the cell membrane from complement-mediated destruction. When a GPI deficit exists, as occurs in PNH, complement can more easily target and lyse the deficient cells. In red blood cells, this results in cell breakdown or hemolysis. The main complement protecting proteins are CD55 which disrupts the formation of CD3 convertase, and CD59
CD59
Protectin, a complement regulatory protein, also known as ', or MIRL is a human gene and protein....
, which binds the membrane attack complex and prevents C-9
Complement component 9
Complement component 9 is a protein involved in the complement system....
from binding to the cell, and inducing cell breakdown. Eculizumab targets C5 and thus inhibits the complement system from destroying the otherwise vulnerable CD55 and CD59 deficient blood cells of PNH patients, producing a rapid and substantial reduction in hemolysis in almost all treated patients.
PNH
In a double-blind, randomized, placebo-controlled Phase III trial (TRIUMPH), with 87 patients, eculizumab was found to deliver an 86% reduction of intravascular hemolysis as measured by LDH reduction. It also permitted a 73% reduction in transfusions across all subgroups. Notably, there was a rapid and meaningful improvement in fatigue and quality of life for the treated patients. No serious treatment-related adverse events were encountered.Significantly, data from three independent parent clinical studies (Phase II pilot study, Phase III TRIUMPH study, and Phase III SHEPHERD study) demonstrated a greater than 90% reduction in thromboembolic events, the most serious complication and major cause of death in PNH. All PNH patients in clinical trials showed a benefit from eculizumab therapy – many benefits occurred rapidly; others showed improvement over time.
Investigational Uses
There are case reports of eculizumab being used to treat congenital atypical hemolytic uremic syndrome, as well as severe shiga-toxin associated hemolytic uremic syndrome, such as occurred during the May 2011 outbreak of enterohemorrhagic E. coli in Germany. Eculizumab was given in an attempt to block dysregulated complement activation, which is thought to play a role in the pathogenesis of both of these forms of hemolytic uremic syndrome.There are also reports of eculizumab being used to treat cold agglutinin disease. In one patient cast report, eculizumab led to a sustained reduction of hemolysis, disappearance of further exacerbations, complete elimination of transfusion requirements and improvement of symptoms and quality of life.
Early results from a Mayo Clinic research study demonstrate the effectiveness of a new approach to blocking an important part of the immune system that causes severe damage to some kidney transplants
Kidney transplantation
Kidney transplantation or renal transplantation is the organ transplant of a kidney into a patient with end-stage renal disease. Kidney transplantation is typically classified as deceased-donor or living-donor transplantation depending on the source of the donor organ...
. Results show that eculizumab prevents antibody-mediated kidney transplant rejection by inhibiting the immune system's activation of one of the body's important defense mechanisms — the complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
.
Eculizumab is well tolerated, with headache the most common adverse event on initiation of treatment.
Dosing
The recommended dosage regimen is:- 600mg IV weekly x 4 weeks, followed by
- 900mg IV for the fifth dose 1 week later, followed by
- 900mg IV every two weeks thereafter.
It is administered by intravenous infusion over 35 minutes. Patients are followed and monitored for response with LDH
LDH
LDH is an acronym which may refer to:* Lactate dehydrogenase, an enzyme in a wide range of plants, animals and other organisms; is measured as part of the complete blood test* Large diameter hose, a type of fire hose...
(measure of intravascular hemolysis), hemoglobin level (transfusion requirement), infection monitoring, and thromboembolism incidence.
Efficacy
A study of 79 patients treated with eculizumab at the Leeds PNH Center, suggests that the agent is effective in preventing new, or evolution of pre-existing thrombosis and appears to remove the need for primary prophylactic anticoagulation. The authors, however, pointed out that anticoagulation was not systematically stopped in patients with a previous history of thrombosis. This landmark study demonstrated that eculizumab was a well tolerated long-term therapy (>8 years), with continued improvement in PNH symptoms, a significant reduction in transfusion requirements, and a significant reduction in thromboembolism. Most importantly, it demonstrated that eculizumab has a major impact on survival, rendering patient survival comparable to an age and sex matched control population, dramatically improved from the pre-eculizumab era.Safety
Eculizumab inhibits complementComplement
In many different fields, the complement of X is something that together with X makes a complete whole—something that supplies what X lacks.Complement may refer to:...
activation and therefore makes patients vulnerable to infection with encapsulated organisms. Serious meningococcus infections have been described in patients who received eculizumab. Due to the increased risk of meningococcal infections, meningococcal vaccination
Meningococcal vaccine
Meningococcal vaccine is a vaccine used against Meningococcus, a bacterium that causes meningitis, meningococcemia, septicemia, and rarely carditis, septic arthritis, or pneumonia.-Types:...
is recommended at least 2 weeks prior to receiving eculizumab. There is concern, however, that current meningococcal vaccines may not be sufficient to protect patients, since commonly available vaccines do not protect against strains of meningococcus with a serogroup B antigen, which is prevalent in countries such as the Netherlands.