alemtuzumab

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.{{cite web|url=http://www.campath.com/hcp/AboutCampath.html |title=About Campath |publisher=Genzyme |url-status=dead |archive-url=https://web.archive.org/web/20110714063804/http://www.campath.com/hcp/AboutCampath.html |archive-date=2011-07-14 }}{{Unreliable medical source|date=January 2024}}

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.{{cite journal | vauthors = Zhang J, Shi S, Zhang Y, Luo J, Xiao Y, Meng L, Yang X | title = Alemtuzumab versus interferon beta 1a for relapsing-remitting multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 11 | issue = 11 | pages = CD010968 | date = November 2017 | pmid = 29178444 | pmc = 6486233 | doi = 10.1002/14651858.CD010968.pub2 }} 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.

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.

In November 2018, the US Food and Drug Administration (FDA) issued a safety announcement{{cite web | title = FDA warns about rare but serious risks of stroke and blood vessel wall tears with multiple sclerosis drug Lemtrada (alemtuzumab) | work = FDA Drug Safety Communication | publisher = U.S. Food and Drug Administration (FDA) | date = 29 November 2018 | url = https://www.fda.gov/media/118875/download }} 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.{{cite journal | vauthors = Azevedo CJ, Kutz C, Dix A, Boster A, Sanossian N, Kaplan J | title = Intracerebral haemorrhage during alemtuzumab administration | journal = The Lancet. Neurology | volume = 18 | issue = 4 | pages = 329–331 | date = April 2019 | pmid = 30777657 | doi = 10.1016/S1474-4422(19)30076-6 | s2cid = 72334305 }}

In April 2019, the [https://www.ema.europa.eu/en/committees/pharmacovigilance-risk-assessment-committee-prac Pharmacovigilance Risk Assessment Committee] (PRAC) of the European Medicines Agency (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.{{cite web | title = Use of multiple sclerosis medicine Lemtrada restricted while PRAC review is ongoing | work = Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) | publisher = European Medicines Agency | date = 12 April 2019 | url = https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-8-11-april-2019}}

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.{{cite web|url=https://www.medicines.org.uk/emc/product/5409#UNDESIRABLE_EFFECTS|title=LEMTRADA 12 mg concentrate for solution for infusion - Summary of Product Characteristics (SMPC) - (Emc)|access-date=7 April 2019|archive-date=6 May 2021|archive-url=https://web.archive.org/web/20210506131642/https://www.medicines.org.uk/emc/product/5409#UNDESIRABLE_EFFECTS|url-status=dead}} The Summary of Product Characteristics provided in the electronic Medicines Compendium [eMC {{Cite web|url=https://www.medicines.org.uk/emc/|title=Home - electronic medicines compendium (emc)|website=www.medicines.org.uk|accessdate=16 February 2024}}] further lists common and uncommon adverse reactions that have been reported for Lemtrada, which include serious opportunistic nocardial infections and cytomegalovirus syndrome.{{cite journal | vauthors = Sheikh-Taha M, Corman LC | title = Pulmonary Nocardia beijingensis infection associated with the use of alemtuzumab in a patient with multiple sclerosis | journal = Multiple Sclerosis | volume = 23 | issue = 6 | pages = 872–874 | date = May 2017 | pmid = 28290754 | doi = 10.1177/1352458517694431 | s2cid = 206702778 }}{{cite journal | vauthors = Clerico M, De Mercanti S, Artusi CA, Durelli L, Naismith RT | title = Active CMV infection in two patients with multiple sclerosis treated with alemtuzumab | journal = Multiple Sclerosis | volume = 23 | issue = 6 | pages = 874–876 | date = May 2017 | pmid = 28290755 | doi = 10.1177/1352458516688350 | s2cid = 206702649 }}{{cite journal | vauthors = Brownlee WJ, Chataway J | title = Opportunistic infections after alemtuzumab: New cases of norcardial infection and cytomegalovirus syndrome | journal = Multiple Sclerosis | volume = 23 | issue = 6 | pages = 876–877 | date = May 2017 | pmid = 28290753 | doi = 10.1177/1352458517693440 | s2cid = 30519152 | url = https://discovery.ucl.ac.uk/id/eprint/1537542/ }}

Alemtuzumab can also precipitate autoimmune disease through the suppression of regulatory T cell populations and/or the emergence of autoreactive B-cells.{{cite journal | vauthors = Costelloe L, Jones J, Coles A | title = Secondary autoimmune diseases following alemtuzumab therapy for multiple sclerosis | journal = Expert Review of Neurotherapeutics | volume = 12 | issue = 3 | pages = 335–341 | date = March 2012 | pmid = 22364332 | doi = 10.1586/ern.12.5 | s2cid = 34738692 }}{{cite journal | vauthors = Aranha AA, Amer S, Reda ES, Broadley SA, Davoren PM | title = Autoimmune thyroid disease in the use of alemtuzumab for multiple sclerosis: a review | journal = Endocrine Practice | volume = 19 | issue = 5 | pages = 821–828 | date = 2013 | pmid = 23757618 | doi = 10.4158/EP13020.RA }}

Cases of multiple sclerosis reactivation/relapse have also been reported{{cite journal | vauthors = Wehrum T, Beume LA, Stich O, Mader I, Mäurer M, Czaplinski A, Weiller C, Rauer S | title = Activation of disease during therapy with alemtuzumab in 3 patients with multiple sclerosis | journal = Neurology | volume = 90 | issue = 7 | pages = e601–e605 | date = February 2018 | pmid = 29352101 | doi = 10.1212/WNL.0000000000004950 | s2cid = 3319939 }}

Alemtuzumab is a recombinant DNA-derived humanized IgG1 kappa monoclonal antibody that is directed against the cell surface glycoprotein CD52.{{cite journal| vauthors = Klement A | date = 7 January 2014| title = Multiple-Sklerose-Behandlung| journal = Österreichische Apothekerzeitung| issue = 1/2014| page = 24f| language = de}}

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.{{cite journal | vauthors = Hale G, Bright S, Chumbley G, Hoang T, Metcalf D, Munro AJ, Waldmann H | title = Removal of T cells from bone marrow for transplantation: a monoclonal antilymphocyte antibody that fixes human complement | journal = Blood | volume = 62 | issue = 4 | pages = 873–882 | date = October 1983 | pmid = 6349718 | doi = 10.1182/blood.V62.4.873.873 | doi-access = free | title-link = doi }} The name Campath derives from the pathology department of Cambridge University.

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.{{cite journal | vauthors = Riechmann L, Clark M, Waldmann H, Winter G | title = Reshaping human antibodies for therapy | journal = Nature | volume = 332 | issue = 6162 | pages = 323–327 | date = March 1988 | pmid = 3127726 | doi = 10.1038/332323a0 | s2cid = 4335569 | doi-access = free | title-link = doi | bibcode = 1988Natur.332..323R }}

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.{{cite web|url=http://www.whatisbiotechnology.org/exhibitions/campath|title=The life story of a biotechnology drug: Alemtuzumab|publisher=What is Biotechnology?}}

Campath as a medication was first approved for B-cell chronic lymphocytic leukemia in 2001. It is marketed by Genzyme, which acquired the worldwide rights from Bayer AG in 2009. Genzyme was bought by Sanofi 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 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.{{cite news | title=Sanofi withdraws Campath in US and EU | vauthors=McKee S | date=21 August 2012 | work=Pharma Times Online | publisher=Pharma Times | url=http://www.pharmatimes.com/Article/12-08-21/Sanofi_withdraws_Campath_in_US_and_EU.aspx | access-date=6 November 2012 | archive-date=4 March 2016 | archive-url=https://web.archive.org/web/20160304031613/http://www.pharmatimes.com/Article/12-08-21/Sanofi_withdraws_Campath_in_US_and_EU.aspx | url-status=dead }}

In February 2011, Sanofi-Aventis, since renamed Sanofi, acquired Genzyme, the manufacturer of alemtuzumab.{{cite news | title=Sanofi Buys Genzyme for over $20 billion | date=17 February 2011 | vauthors = Whalen J, Spencer M | url=https://www.wsj.com/articles/SB10001424052748703373404576147483489656732 | work=The Wall Street Journal | url-access = subscription}} 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,{{cite web | title=Discontinuation of licensed supplies of alemtuzumab (Mabcampath) | vauthors = Hussein J | url = http://www.medicinesresources.nhs.uk/upload/documents/News/2012/Sanofil%20letter.pdf | publisher=National Institute for Health and Care Excellence | location=United Kingdom | date=9 August 2012 }} pending regulatory approval to reintroduce it as a treatment for multiple sclerosis. Concerns{{cite news|title=Multiple sclerosis: New drug 'most effective'|url=https://www.bbc.co.uk/news/health-20151891|access-date=1 November 2012|newspaper=BBC News|date=1 November 2012}} that Genzyme would later bring to market the same product at a much higher price proved correct.

Alemtuzumab is the international nonproprietary name.{{cite journal | vauthors = ((World Health Organization)) | year = 2023 | title = International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 90 | journal = WHO Drug Information | volume = 37 | issue = 3 | hdl = 10665/373341 | hdl-access = free | author-link = World Health Organization }}

In an in-vitro experiment, it has been shown that alemtuzumab has antiviral properties against HIV-1.{{cite journal | vauthors = Ruxrungtham K, Sirivichayakul S, Buranapraditkun S, Krause W | title = Alemtuzumab-induced elimination of HIV-1-infected immune cells | journal = Journal of Virus Eradication | volume = 2 | issue = 1 | pages = 12–18 | date = January 2016 | pmid = 27482429 | pmc = 4946689 | doi = 10.1016/S2055-6640(20)30694-4 }}

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 after allogeneic hematopoietic stem cell transplantation (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 reactivation, bacterial infection, and invasive aspergillosis infection.{{cite journal | vauthors = Schnitzler M, Hasskarl J, Egger M, Bertz H, Finke J | title = Successful treatment of severe acute intestinal graft-versus-host resistant to systemic and topical steroids with alemtuzumab | journal = Biology of Blood and Marrow Transplantation | volume = 15 | issue = 8 | pages = 910–918 | date = August 2009 | pmid = 19589480 | doi = 10.1016/j.bbmt.2009.04.002 | doi-access = free | title-link = doi }}

{{reflist}}

• [http://users.path.ox.ac.uk/~scobbold/tig/CAMPATH/CAMPHIST.HTM From laboratory to clinic: the story of CAMPATH-1 (Geoff Hale and Herman Waldmann)]
• {{cite web | title=Alemtuzumab | website=National Cancer Institute | date=30 November 2007 | url=https://www.cancer.gov/about-cancer/treatment/drugs/alemtuzumab }}

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