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Alemtuzumab, sold under the brand names Campath and Lemtrada among others, is a
medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
used to treat
chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow. In CLL, the bone marrow makes too many lymphocytes, which are a type of white blood cell. In patients with CLL, B cell lymphocytes can begin to colle ...
and
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
. In chronic lymphocytic leukemia, it has been used as both a first line and second line treatment. It is given by
injection into a vein Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
. It is a
monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodie ...
that binds to CD52, a protein present on the surface of mature
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...
s, but not on the
stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...
s from which these lymphocytes are derived. After treatment with alemtuzumab, these CD52-bearing lymphocytes are targeted for destruction. Alemtuzumab was approved for medical use in the United States in 2001. (Mab)Campath was withdrawn from the markets in the US and the EU in 2012, to prepare for a higher-priced relaunch of Lemtrada aimed at multiple sclerosis.


Medical uses


Chronic lymphocytic leukemia

Alemtuzumab is used for the treatment of B-cell chronic lymphocytic leukemia in people 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 Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of Cell-mediated immunity, cell-mediated immune defense whereby an effector cell of the immune system kills a target ...
.


Multiple sclerosis

It is used for the relapsing remitting form of multiple sclerosis. A 2017 Cochrane meta-analysis of studies comparing alemtuzumab to interferon beta 1a concluded that annual cycles of alemtuzumab probably reduces the proportion of people that experience relapse and may reduce the proportion of people who experience disability worsening and new T2 lesions on MRI, with adverse events found to be similarly high for both treatments. However the low-to-moderate levels of evidence in the included, existing studies were noted and the need for larger high-quality randomised, double-blind, controlled trials comparing mono or combination therapy with alemtuzumab was highlighted.


Contraindications

Alemtuzumab is contraindicated in patients who have active infections, underlying immunodeficiency (e.g., seropositive for HIV), or known type I hypersensitivity or anaphylactic reactions to the substance.


Adverse effects

In November 2018, the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) issued a safety announcement warning about rare but serious instances of stroke and blood vessel wall tears in multiple sclerosis patients who have received Lemtrada (alemtuzumab), mostly occurring within one day of initiating treatment and leading in some cases to permanent disability and even death. In addition to the 13 cases to which the FDA safety announcement refers, a further five cases of spontaneous intracranial hemorrhage have been retrospectively identified from four US multiple sclerosis centers in correspondence published online in February 2019. In April 2019, th
Pharmacovigilance Risk Assessment Committee
(PRAC) of the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
(EMA) reported that it has started a review of the multiple sclerosis medicine Lemtrada (alemtuzumab) following new reports of immune-mediated conditions and of problems with the heart and blood vessels with this medicine, including fatal cases. The PRAC advised that while the review is ongoing, Lemtrada should only be started in adults with relapsing-remitting multiple sclerosis that is highly active despite treatment with at least two disease-modifying therapies (a type of multiple sclerosis medicine) or where other disease-modifying therapies cannot be used. The PRAC further advised that patients being treated with Lemtrada who are benefitting from it may continue treatment in consultation with their doctor. Very common adverse reactions associated with alemtuzumab infusion in people with multiple sclerosis include upper respiratory tract and urinary tract infections, herpes virus infections, lymphopenia, leucopenia, changes in thyroid function, tachycardia, skin rashes, pruritus, pyrexia, and fatigue. The Summary of Product Characteristics provided in the electronic Medicines Compendium MC further lists common and uncommon adverse reactions that have been reported for Lemtrada, which include serious opportunistic nocardial infections and cytomegalovirus syndrome. Alemtuzumab can also precipitate
autoimmune disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
through the suppression of
regulatory T cell The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain immune tolerance, tolerance to self-antigens, and prevent autoimmune disease. Treg  ...
populations and/or the emergence of autoreactive B-cells. Cases of multiple sclerosis reactivation/relapse have also been reported


Biochemical properties

Alemtuzumab is a recombinant DNA-derived humanized IgG1 kappa monoclonal antibody that is directed against the cell surface glycoprotein CD52.


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 and colleagues in 1983. The name Campath derives from the ''path''ology department of
Cambridge University The University of Cambridge is a Public university, public collegiate university, collegiate research university in Cambridge, England. Founded in 1209, the University of Cambridge is the List of oldest universities in continuous operation, wo ...
. 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 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. While alemtuzumab started life as a laboratory tool for understanding the immune system, within a short time it was clinically investigated for use to improve the success of bone marrow transplants and as a treatment for leukaemia, lymphoma, vasculitis, organ transplants, rheumatoid arthritis and multiple sclerosis.


Society and culture


Economics

Campath as a medication was first approved for B-cell chronic lymphocytic leukemia in 2001. It is marketed by
Genzyme Genzyme (also known as Genzyme Transgenics Corp or GTC Biotherapeutics) was an American biotechnology company based in Cambridge, Massachusetts. From its acquisition in 2011 to 2022 Genzyme operated as a fully owned subsidiary of Sanofi. In 2010, ...
, which acquired the worldwide rights from
Bayer AG Bayer AG (English: , commonly pronounced ; ) is a German multinational pharmaceutical and biotechnology company and is one of the largest pharmaceutical companies and biomedical companies in the world. Headquartered in Leverkusen, Bayer's ...
in 2009. Genzyme was bought by
Sanofi Sanofi S.A. is a French Multinational corporation, multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 200 ...
in 2011. In August/September 2012 Campath was withdrawn from the markets in the US and EU. This was done to prevent
off-label use Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although mo ...
of the drug to treat multiple sclerosis and to prepare for a relaunch under the brand name Lemtrada, with a different dosage aimed at multiple sclerosis treatment, this is expected to be much higher-priced. In February 2011, Sanofi-Aventis, since renamed
Sanofi Sanofi S.A. is a French Multinational corporation, multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 200 ...
, acquired Genzyme, the manufacturer of alemtuzumab. The acquisition was delayed by a dispute between the two companies regarding the value of alemtuzumab. In August 2012, Genzyme surrendered the license for all presentations of alemtuzumab, pending regulatory approval to reintroduce it as a treatment for
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
. Concerns that Genzyme would later bring to market the same product at a much higher price proved correct.


Names

Alemtuzumab is the international nonproprietary name.


Research


Antiviral properties

In an in-vitro experiment, it has been shown that alemtuzumab has antiviral properties against
HIV-1 The subtypes of HIV include two main subtypes, known as HIV type 1 (HIV-1) and HIV type 2 (HIV-2). These subtypes have distinct genetic differences and are associated with different epidemiological patterns and clinical characteristics. HIV-1 e ...
.


Graft-versus-host disease

A 2009 retrospective study of alemtuzumab (10 mg IV weekly) in 20 patients (no controls) with severe steroid-resistant acute intestinal
graft-versus-host disease Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants. White blood cells of the donor's immune system which rema ...
after allogeneic
hematopoietic stem cell transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce ...
(HSCT) 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'' (CMV) (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order '' Herpesvirales'', in the family '' Herpesviridae'', in the subfamily '' Betaherp ...
reactivation, bacterial infection, and invasive
aspergillosis Aspergillosis is a fungal infection of usually the lungs, caused by the genus ''Aspergillus'', a common mold that is breathed in frequently from the air, but does not usually affect most people. It generally occurs in people with lung diseases su ...
infection.


References


External links


From laboratory to clinic: the story of CAMPATH-1 (Geoff Hale and Herman Waldmann)
* {{Authority control Monoclonal antibodies for tumors Sanofi Withdrawn drugs