OKT3
Encyclopedia
Muromonab-CD3 is an immunosuppressant
drug given to reduce acute rejection in patients with organ transplant
s. It is a monoclonal antibody targeted at the CD3 receptor, a membrane protein
on the surface of T cell
s. It was the first monoclonal antibody to be approved
for clinical use in humans.
, it was the first drug to be approved under the directive 87/22/EWG, a precursor of the European Medicines Agency
(EMEA) centralised approval system in the European Union
. This process included an assessment by the Committee for Proprietary Medicinal Products (CPMP, now CHMP), and a subsequent approval by the national health agencies; in Germany
, for example, in 1988 by the Paul Ehrlich Institute in Frankfurt
.
resistant rejection of allogeneic
renal, heart and liver transplants. Unlike the monoclonal antibodies basiliximab
and daclizumab
, it is not approved for prophylaxis of transplant rejection, although a 1996 review has found it to be safe for that purpose.
It has also been investigated for use in treating T-cell acute lymphoblastic leukemia
.
s primarily via the T cell receptor
. This receptor needs various co-receptors to function, one of which is CD3. The T cell receptor-CD3 complex transduces the signal for the T cell to proliferate and attack the antigen.
Muromonab-CD3 is a murine (mouse) monoclonal IgG2a antibody which was created using hybridoma technology. It binds to the T cell receptor-CD3-complex (specifically the CD3 epsilon chain) on the surface of circulating T cells, initially leading to an activation, but subsequently inducing blockage and apoptosis
of the T cells. This protects the transplant against the T cells.
After application of muromonab-CD3, normal T cell function is said to be restored within a week. When administered for transplant induction, the drug is administered daily thereafter for up to 7 days.
Newer monoclonal antibodies with the same mechanism of action include otelixizumab
, teplizumab
and visilizumab
. They are being investigated for the treatment of other conditions like Crohn's disease
, ulcerative colitis
and type 1 diabetes.
and interferon gamma. This cytokine release syndrome
, or CRS, includes side effects like skin reactions, fatigue, fever
, chills, myalgia
, headaches, nausea
and diarrhea
, and could lead to life-threatening conditions like apnoea, cardiac arrest
, and flash pulmonary edema
. To minimize the risk of CRS and to offset some of the minor side effects patient experience, glucocorticoid
s (such as methylprednisolone
), acetaminophen, and diphenhydramine
are given before the infusion.
Other adverse effects include leucopenia, as well as an increased risk for severe infections and malignancies typical of immunosuppressive therapies. Neurological
side effects like aseptic meningitis
and encephalopathy
have been observed. Possibly, they are also caused by the T cell activation.
Repeated application can result in tachyphylaxis
(reduced effectiveness) due to the formation of anti-mouse antibodies in the patient, which accelerates elimination of the drug. It can also lead to an anaphylactic reaction against the mouse protein, which may be difficult to distinguish from a CRS.
. It should not be used during pregnancy
or lactation
.
nomenclature of monoclonal antibodies
took effect, and consequently its name does not follow this convention. Instead, it is a contraction from "murine monoclonal antibody targeting CD3".
Immunosuppressant
An immunosuppressant is any substance that performs immunosuppression of the immune system. They may be either exogenous, as immunosuppressive drugs, or endogenous, as ,e. g., testosterone...
drug given to reduce acute rejection in patients with organ transplant
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
s. It is a monoclonal antibody targeted at the CD3 receptor, a membrane protein
Membrane protein
A membrane protein is a protein molecule that is attached to, or associated with the membrane of a cell or an organelle. More than half of all proteins interact with membranes.-Function:...
on the surface of T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s. It was the first monoclonal antibody to be approved
Regulation of therapeutic goods
The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency...
for clinical use in humans.
History
Muromonab-CD3 was approved by the U.S. Food and Drug Administration (FDA) in 1986, making it the first monoclonal antibody to be approved anywhere as a drug for humans. In the European CommunitiesEuropean Communities
The European Communities were three international organisations that were governed by the same set of institutions...
, it was the first drug to be approved under the directive 87/22/EWG, a precursor of 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...
(EMEA) centralised approval system in the European Union
European Union
The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...
. This process included an assessment by the Committee for Proprietary Medicinal Products (CPMP, now CHMP), and a subsequent approval by the national health agencies; in Germany
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
, for example, in 1988 by the Paul Ehrlich Institute in Frankfurt
Frankfurt
Frankfurt am Main , commonly known simply as Frankfurt, is the largest city in the German state of Hesse and the fifth-largest city in Germany, with a 2010 population of 688,249. The urban area had an estimated population of 2,300,000 in 2010...
.
Indications
Muromonab-CD3 is approved for the therapy of acute, glucocorticoidGlucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
resistant rejection of allogeneic
Allotransplantation
Allotransplantation is the transplantation of cells, tissues, or organs, sourced from a genetically non-identical member of the same species as the recipient. The transplant is called an allograft or allogeneic transplant or homograft...
renal, heart and liver transplants. Unlike the monoclonal antibodies basiliximab
Basiliximab
Basiliximab is a chimeric mouse-human monoclonal antibody to the α chain of the IL-2 receptor of T cells. It is used to prevent rejection in organ transplantation, especially in kidney transplants...
and daclizumab
Daclizumab
Daclizumab is a therapeutic humanized monoclonal antibody to the alpha subunit of the IL-2 receptor of T cells. It is used to prevent rejection in organ transplantation, especially in kidney transplants....
, it is not approved for prophylaxis of transplant rejection, although a 1996 review has found it to be safe for that purpose.
It has also been investigated for use in treating T-cell acute lymphoblastic leukemia
T-cell acute lymphoblastic leukemia
T-cell acute lymphoblastic leukemia can refer to:* Precursor T acute lymphoblastic leukemia/lymphoma* Adult T-cell leukemia/lymphoma...
.
Pharmacodynamics and chemistry
T cells recognise antigenAntigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s primarily via the T cell receptor
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
. This receptor needs various co-receptors to function, one of which is CD3. The T cell receptor-CD3 complex transduces the signal for the T cell to proliferate and attack the antigen.
Muromonab-CD3 is a murine (mouse) monoclonal IgG2a antibody which was created using hybridoma technology. It binds to the T cell receptor-CD3-complex (specifically the CD3 epsilon chain) on the surface of circulating T cells, initially leading to an activation, but subsequently inducing blockage and 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...
of the T cells. This protects the transplant against the T cells.
After application of muromonab-CD3, normal T cell function is said to be restored within a week. When administered for transplant induction, the drug is administered daily thereafter for up to 7 days.
Newer monoclonal antibodies with the same mechanism of action include otelixizumab
Otelixizumab
Otelixizumab, also known as TRX4, is a monoclonal antibody, which is being developed for the treatment of type 1 diabetes and other autoimmune diseases. The antibody is being developed by Tolerx, Inc...
, teplizumab
Teplizumab
Teplizumab is a monoclonal antibody which is used as an immunosuppressive drug.Teplizumab is a humanized Fc-engineered monoclonal antibody also known as MGA031 and hOKT3γ1....
and visilizumab
Visilizumab
Visilizumab is a humanized monoclonal antibody. It is being investigated for use as an immunosuppressive drug in patients with ulcerative colitis and Crohn's disease. Visilizumab binds to the CD3 receptor on certain activated T cells without affecting resting T cells...
. They are being investigated for the treatment of other conditions like Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
, ulcerative colitis
Ulcerative colitis
Ulcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the colon , that includes characteristic ulcers, or open sores. The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual onset...
and type 1 diabetes.
Adverse effects
Especially during the first infusion, the binding of muromonab-CD3 to CD3 can activate T cells to release cytokines like tumor necrosis factorTumor necrosis factor
Tumor necrosis factor is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction...
and interferon gamma. This cytokine release syndrome
Cytokine release syndrome
Cytokine release syndrome is a common immediate complication occurring with the use of anti-T cell antibody infusions such as ATG, OKT3 and TGN1412. Severe cases are known as cytokine storms....
, or CRS, includes side effects like skin reactions, fatigue, 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...
, chills, myalgia
Myalgia
Myalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections...
, headaches, nausea
Nausea
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...
and 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...
, and could lead to life-threatening conditions like apnoea, cardiac arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
, and flash pulmonary edema
Flash pulmonary edema
In medicine, flash pulmonary edema , is rapid onset pulmonary edema. It is most often precipitated by acute myocardial infarction or mitral regurgitation, but can be caused by aortic regurgitation, heart failure, or almost any cause of elevated left ventricular filling pressures...
. To minimize the risk of CRS and to offset some of the minor side effects patient experience, glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s (such as methylprednisolone
Methylprednisolone
Methylprednisolone is a synthetic glucocorticoid or corticosteroid drug. It is marketed in the USA and Canada under the brand names Medrol and Solu-Medrol. It is also available as a generic drug....
), acetaminophen, and diphenhydramine
Diphenhydramine
Diphenhydramine hydrochloride is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason...
are given before the infusion.
Other adverse effects include leucopenia, as well as an increased risk for severe infections and malignancies typical of immunosuppressive therapies. Neurological
Neurology
Neurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...
side effects like aseptic meningitis
Aseptic meningitis
Aseptic meningitis, or sterile meningitis, is a condition in which the layers lining the brain, meninges, become inflamed and a pyogenic bacterial source is not to blame. Meningitis is diagnosed on a history of characteristic symptoms and certain examination findings...
and encephalopathy
Encephalopathy
Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...
have been observed. Possibly, they are also caused by the T cell activation.
Repeated application can result in tachyphylaxis
Tachyphylaxis
Tachyphylaxis is a medical term describing a decrease in the response to a drug due to previous exposure to that drug. Increasing the dose of the drug may be able to restore the original response. In this context tachyphylaxis is a synonym for drug tolerance...
(reduced effectiveness) due to the formation of anti-mouse antibodies in the patient, which accelerates elimination of the drug. It can also lead to an anaphylactic reaction against the mouse protein, which may be difficult to distinguish from a CRS.
Contraindications
Except under special circumstances, the drug is contraindicated for patients with an allergy against mouse proteins, as well as patients with uncompensated heart failure, uncontrolled arterial hypertension or epilepsyEpilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
. It should not be used during pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
or lactation
Lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...
.
Etymology
Muromonab-CD3 was developed before the WHOWorld Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
nomenclature of monoclonal antibodies
Nomenclature of monoclonal antibodies
The nomenclature of monoclonal antibodies is a naming scheme for assigning generic, or nonproprietary, names to monoclonal antibodies. An antibody is a protein that is produced in B cells and used by the immune system of humans and other vertebrate animals to identify a specific foreign object like...
took effect, and consequently its name does not follow this convention. Instead, it is a contraction from "murine monoclonal antibody targeting CD3".