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Alemtuzumab

Alemtuzumab

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Alemtuzumab is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia
Chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia , also known as chronic lymphoid leukemia , is the most common type of leukemia. Leukemias are cancers of the white blood cells . CLL affects B cell lymphocytes. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by...

 (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma
Non-Hodgkin lymphoma
The non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....

. It is also used in some conditioning regimens for bone marrow transplantation, kidney transplantation
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...

 and Islet cell transplantation
Islet cell transplantation
Islet transplantation is the transplantation of isolated islets from a donor pancreas and into another person. It is an experimental treatment for type 1 diabetes mellitus. Once transplanted, the islets begin to produce insulin, actively regulating the level of glucose in the blood.Islets are...

.

Alemtuzumab targets CD52
CD52
CD52 is a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes were derived.It also is found in monocytes and dendritic cells....

, a protein present on the surface of mature lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...

s, but not on the stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...

s from which these lymphocytes are derived.

Alemtuzumab is used as second-line therapy for CLL. It was approved by the US 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...

 for CLL patients who have been treated with alkylating agent
Alkylating antineoplastic agent
An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group to DNA.The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring....

s and who have failed fludarabine
Fludarabine
Fludarabine or fludarabine phosphate is a chemotherapy drug used in the treatment of hematological malignancies. It has been unofficially and casually referred to as "AIDS in a bottle" amongst healthcare professionals due to its significant immunosuppresive activity.-Indications:Fludarabine is...

 therapy. It has been approved by Health Canada
Health Canada
Health Canada is the department of the government of Canada with responsibility for national public health.The current Minister of Health is Leona Aglukkaq, a Conservative Member of Parliament appointed to the position by Prime Minister Stephen Harper.-Branches, regions and agencies:Health Canada...

 for the same indication, and additionally for CLL patients who have not had any previous therapies.

It is also used under clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

 protocols for treatment of some autoimmune diseases, such as 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...

, in which it shows promise.
A significant complication of therapy with alemtuzumab is that it significantly increases the risk for opportunistic infection
Opportunistic infection
An opportunistic infection is an infection caused by pathogens, particularly opportunistic pathogens—those that take advantage of certain situations—such as bacterial, viral, fungal or protozoan infections that usually do not cause disease in a healthy host, one with a healthy immune system...

s, in particular, reactivation of cytomegalovirus
Cytomegalovirus
Cytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...

.

Description


Alemtuzumab (Campath-1H) is a recombinant DNA-derived humanized monoclonal antibody that is directed against the 21–28 kDa cell surface glycoprotein, CD52.

Indications and use


Alemtuzumab is indicated for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy. It is an unconjugated antibody, thought to work via the activation of antibody-dependent cell-mediated cytotoxicity(ADCC) .

Multiple sclerosis


In 2008 early tests at Cambridge University suggest that alemtuzumab might be useful in treating and even reversing the effects of 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...

. Promising results were reported in 2011 from a phase III trial against Rebif.

Graft-versus-host disease


A 2009 study of alemtuzumab in 20 patients with severe steroid-resistant acute intestinal graft-versus-host disease
Graft-versus-host disease
Graft-versus-host disease is a common complication after a stem cell transplant or bone marrow transplant from another person . Immune cells in the donated marrow or stem cells recognize the recipient as "foreign". The transplanted immune cells then attack the host's body cells...

 after allogeneic hematopoietic cell transplantation (HCT) demonstrated improvement. Overall response rate was 70%, with complete response in 35%. In this study, the median survival was 280 days. Important complications following this treatment included cytomegalovirus
Cytomegalovirus
Cytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...

 reactivation, bacterial infection, and invasive aspergillosis
Aspergillosis
Aspergillosis is the name given to a wide variety of diseases caused by fungi of the genus Aspergillus. The most common forms are allergic bronchopulmonary aspergillosis, pulmonary aspergilloma and invasive aspergillosis. Most humans inhale Aspergillus spores every day...

 infection.

Contraindications and precautions


Alemtuzumab is contraindicated in patients who have active systemic infections, underlying immunodeficiency (e.g., seropositive for HIV), or known Type I hypersensitivity or anaphylactic reactions to Campath or to any one of its components.

Adverse reactions


Alemtuzumab has been associated with infusion-related events including hypotension, rigors, fever, shortness of breath, bronchospasm, chills, and/or rash. In post-marketing reports, the following serious infusion-related events were reported: syncope, pulmonary infiltrates, ARDS, respiratory arrest, cardiac arrhythmias, myocardial infarction and cardiac arrest. The cardiac adverse events have resulted in death in some cases.

It is also possible that perturbation of suppressor T cell populations by Campath-1H may precipitate autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...

.

History


The origins of alemtuzumab date back to Campath-1 which was derived from the rat antibodies raised against human lymphocyte proteins by Herman Waldmann
Herman Waldmann
Herman Waldmann FRS FMedSci is a British immunologist known for his work on therapeutic monoclonal antibodies. As of 2010, he heads the Sir William Dunn School of Pathology at the University of Oxford.-Career and research:...

 and colleagues. The name "Campath" derives from the pathology department of Cambridge University
University of Cambridge
The University of Cambridge is a public research university located in Cambridge, United Kingdom. It is the second-oldest university in both the United Kingdom and the English-speaking world , and the seventh-oldest globally...

.

Initially, Campath-1 was not ideal for therapy because patients could, in theory, react against the foreign rat protein determinants of the antibody. To circumvent this problem, Greg Winter
Greg Winter
Sir Gregory Winter FRS is a British pioneer of therapeutic monoclonal antibodies. He invented techniques to both humanise and, later, to fully humanise using phage display, antibodies for therapeutic uses...

 and his colleagues humanised Campath-1, by extracting the hypervariable loops that had specificity for CD52 and grafting them onto a human antibody framework. This became known as Campath-1H and serves as the basis for alemtuzumab.

Campath is marketed in the United States and Canada by Genzyme
Genzyme
Genzyme Corporation is a fully owned subsidiary of Sanofi-Aventis. Before its acquisition, Genzyme was an American biotechnology company based in Cambridge, Massachusetts. In 2010, Genzyme was the world’s third-largest biotechnology company, employing more than 11,000 people around the world...

.

External links