Alemtuzumab

Alemtuzumab, sold under the brand names Campath and Lemtrada among others, is a medication used to treat chronic lymphocytic leukemia and multiple sclerosis.^[8] In chronic lymphocytic leukemia, it has been used as both a first line and second line treatment.^[8] It is given by injection into a vein.^[8]

Alemtuzumab

Monoclonal antibody
Type	Whole antibody
Source	Humanized (from rat)
Target	CD52
Clinical data
Trade names	Campath, Mabcampath, Lemtrada, others
AHFS/Drugs.com	Monograph
MedlinePlus	a608053
License data	US DailyMed: Alemtuzumab
Pregnancy category	AU: B3(Lemtrada); B2 (Mabcampath)^[1]^[2]^[3]
Routes of administration	Intravenous infusion
ATC code	L04AG06 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: WARNING^[4]Rx-only^[5]^[6] EU: Rx-only^[7]
Pharmacokinetic data
Elimination half-life	~288 hrs
Identifiers
CAS Number	216503-57-0^Y
DrugBank	DB00087^Y
ChemSpider	none
UNII	3A189DH42V
KEGG	D02802
ChEMBL	ChEMBL1201587^N
Chemical and physical data
Formula	C6468H10066N1732O2005S40
Molar mass	145454.20 g·mol^−1
^NY (what is this?)  (verify)

It is a monoclonal antibody that binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells 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Alemtuzumab was approved for medical use in the United States in 2001.^[8] (Mab)Campath was withdrawn from the markets in the US and the EU in 2012, to prepare for a higher-priced relaunch of Lemtrada aimed at multiple sclerosis.^[9]

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.^{[10][unreliable medical source?]}

Multiple sclerosis

It is used for the relapsing remitting form of multiple sclerosis.^[8] 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.^[11] 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.^[11]

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.^[6]

Adverse effects

In November 2018, the US Food and Drug Administration (FDA) issued a safety announcement^[12] 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.^[13]

In April 2019, the 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.^[14]

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.^[15] The Summary of Product Characteristics provided in the electronic Medicines Compendium [eMC ^[16]] further lists common and uncommon adverse reactions that have been reported for Lemtrada, which include serious opportunistic nocardial infections and cytomegalovirus syndrome.^[17][18][19]

Alemtuzumab can also precipitate autoimmune disease through the suppression of regulatory T cell populations and/or the emergence of autoreactive B-cells.^[20][21]

Cases of multiple sclerosis reactivation/relapse have also been reported^[22]

Biochemical properties

Alemtuzumab is a recombinant DNA-derived humanized IgG1 kappa monoclonal antibody that is directed against the cell surface glycoprotein CD52.^[23]

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.^[24] 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.^[25]

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.^[26]

Society and culture

Economics

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.^[9]

In February 2011, Sanofi-Aventis, since renamed Sanofi, acquired Genzyme, the manufacturer of alemtuzumab.^[27] 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,^[28] pending regulatory approval to reintroduce it as a treatment for multiple sclerosis. Concerns^[29] that Genzyme would later bring to market the same product at a much higher price proved correct.

Names

Alemtuzumab is the international nonproprietary name.^[30]

Research

Antiviral properties

In an in-vitro experiment, it has been shown that alemtuzumab has antiviral properties against HIV-1.^[31]

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 after allogeneic hematopoietic stem cell transplantation (HSCT) demonstrated improvement. Overall response rate was 70%, with complete response in 35%.^[32] In this study, the median survival was 280 days. Important complications following this treatment included cytomegalovirus reactivation, bacterial infection, and invasive aspergillosis infection.^[32]

References

1. "Alemtuzumab Use During Pregnancy". Drugs.com. 22 August 2022. Retrieved 6 January 2024.
2. "TGA eBS - Product and Consumer Medicine Information Licence".
3. "TGA eBS - Product and Consumer Medicine Information Licence".
4. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
5. "Campath- alemtuzumab injection". DailyMed. 3 May 2023. Retrieved 6 January 2024.
6. "Lemtrada- alemtuzumab injection, solution, concentrate". DailyMed. 23 May 2023. Retrieved 6 January 2024.
7. "Lemtrada EPAR". European Medicines Agency. 12 September 2013. Retrieved 6 January 2024.
8. "Alemtuzumab Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 15 July 2019.
9. McKee S (21 August 2012). . Pharma Times Online. Pharma Times. Archived from the original on 4 March 2016. Retrieved 6 November 2012.
10. . Genzyme. Archived from the original on 14 July 2011.
11. Zhang J, Shi S, Zhang Y, Luo J, Xiao Y, Meng L, et al. (November 2017). "Alemtuzumab versus interferon beta 1a for relapsing-remitting multiple sclerosis". The Cochrane Database of Systematic Reviews. 11 (11): CD010968. doi:10.1002/14651858.CD010968.pub2. PMC 6486233. PMID 29178444.
12. "FDA warns about rare but serious risks of stroke and blood vessel wall tears with multiple sclerosis drug Lemtrada (alemtuzumab)". FDA Drug Safety Communication. U.S. Food and Drug Administration (FDA). 29 November 2018.
13. Azevedo CJ, Kutz C, Dix A, Boster A, Sanossian N, Kaplan J (April 2019). "Intracerebral haemorrhage during alemtuzumab administration". The Lancet. Neurology. 18 (4): 329–331. doi:10.1016/S1474-4422(19)30076-6. PMID 30777657. S2CID 72334305.
14. "Use of multiple sclerosis medicine Lemtrada restricted while PRAC review is ongoing". Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC). European Medicines Agency. 12 April 2019.
15. . Archived from the original on 6 May 2021. Retrieved 7 April 2019.
16. "Home - electronic medicines compendium (emc)". www.medicines.org.uk. Retrieved 16 February 2024.
17. Sheikh-Taha M, Corman LC (May 2017). "Pulmonary Nocardia beijingensis infection associated with the use of alemtuzumab in a patient with multiple sclerosis". Multiple Sclerosis. 23 (6): 872–874. doi:10.1177/1352458517694431. PMID 28290754. S2CID 206702778.
18. Clerico M, De Mercanti S, Artusi CA, Durelli L, Naismith RT (May 2017). "Active CMV infection in two patients with multiple sclerosis treated with alemtuzumab". Multiple Sclerosis. 23 (6): 874–876. doi:10.1177/1352458516688350. PMID 28290755. S2CID 206702649.
19. Brownlee WJ, Chataway J (May 2017). "Opportunistic infections after alemtuzumab: New cases of norcardial infection and cytomegalovirus syndrome". Multiple Sclerosis. 23 (6): 876–877. doi:10.1177/1352458517693440. PMID 28290753. S2CID 30519152.
20. Costelloe L, Jones J, Coles A (March 2012). "Secondary autoimmune diseases following alemtuzumab therapy for multiple sclerosis". Expert Review of Neurotherapeutics. 12 (3): 335–341. doi:10.1586/ern.12.5. PMID 22364332. S2CID 34738692.
21. Aranha AA, Amer S, Reda ES, Broadley SA, Davoren PM (2013). "Autoimmune thyroid disease in the use of alemtuzumab for multiple sclerosis: a review". Endocrine Practice. 19 (5): 821–828. doi:10.4158/EP13020.RA. PMID 23757618.
22. Wehrum T, Beume LA, Stich O, Mader I, Mäurer M, Czaplinski A, et al. (February 2018). "Activation of disease during therapy with alemtuzumab in 3 patients with multiple sclerosis". Neurology. 90 (7): e601–e605. doi:10.1212/WNL.0000000000004950. PMID 29352101. S2CID 3319939.
23. Klement A (7 January 2014). "Multiple-Sklerose-Behandlung". Österreichische Apothekerzeitung (in German) (1/2014): 24f.
24. Hale G, Bright S, Chumbley G, Hoang T, Metcalf D, Munro AJ, et al. (October 1983). "Removal of T cells from bone marrow for transplantation: a monoclonal antilymphocyte antibody that fixes human complement". Blood. 62 (4): 873–882. doi:10.1182/blood.V62.4.873.873. PMID 6349718.
25. Riechmann L, Clark M, Waldmann H, Winter G (March 1988). "Reshaping human antibodies for therapy". Nature. 332 (6162): 323–327. Bibcode:1988Natur.332..323R. doi:10.1038/332323a0. PMID 3127726. S2CID 4335569.
26. "The life story of a biotechnology drug: Alemtuzumab". What is Biotechnology?.
27. Whalen J, Spencer M (17 February 2011). "Sanofi Buys Genzyme for over $20 billion". The Wall Street Journal.
28. Hussein J (9 August 2012). "Discontinuation of licensed supplies of alemtuzumab (Mabcampath)" (PDF). United Kingdom: National Institute for Health and Care Excellence.
29. "Multiple sclerosis: New drug 'most effective'". BBC News. 1 November 2012. Retrieved 1 November 2012.
30. World Health Organization (2023). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 90". WHO Drug Information. 37 (3). hdl:10665/373341.
31. Ruxrungtham K, Sirivichayakul S, Buranapraditkun S, Krause W (January 2016). "Alemtuzumab-induced elimination of HIV-1-infected immune cells". Journal of Virus Eradication. 2 (1): 12–18. doi:10.1016/S2055-6640(20)30694-4. PMC 4946689. PMID 27482429.
32. Schnitzler M, Hasskarl J, Egger M, Bertz H, Finke J (August 2009). "Successful treatment of severe acute intestinal graft-versus-host resistant to systemic and topical steroids with alemtuzumab". Biology of Blood and Marrow Transplantation. 15 (8): 910–918. doi:10.1016/j.bbmt.2009.04.002. PMID 19589480.

External links

• From laboratory to clinic: the story of CAMPATH-1 (Geoff Hale and Herman Waldmann)
• "Alemtuzumab". National Cancer Institute. 30 November 2007.