Alemtuzumab

Alemtuzumab (marketed as Campath, MabCampath or Campath-1H and currently under further development as Lemtrada) is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma. It is also used in some conditioning regimens for bone marrow transplantation, kidney transplantation and Islet cell transplantation.

Alemtuzumab 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 is used as second-line therapy for CLL. It was approved by the US Food and Drug Administration for CLL patients who have been treated with alkylating agents and who have failed fludarabine therapy. It has been approved by 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 protocols for treatment of some autoimmune diseases, such as multiple sclerosis, in which it shows promise. Alemtuzumab was withdrawn from the markets in the US and Europe in 2012 to prepare for a higher-priced relaunch aimed at multiple sclerosis.

A complication of therapy with alemtuzumab is that it significantly increases the risk for opportunistic infections, in particular, reactivation of cytomegalovirus.

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).

Change of license controversy
In August 2012, Genzyme surrendered the licence for all presentations of alemtuzumab, pending regulatory approval to re-introduce it as a treatment for multiple sclerosis. There is concern that Genzyme will use this as an excuse to market the same product at a much higher price than the current tariff.

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. Promising results were reported in 2011 from a phase III trial against Rebif. A combination trial with Copaxone is being considered, and is expected to work synergistically.

Graft-versus-host disease
A 2009 study of alemtuzumab in 20 patients with severe steroid-resistant acute intestinal graft-versus-host disease 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 reactivation, bacterial infection, and invasive aspergillosis 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.

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 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.

Campath as medication was first approved in 2001. It is marketed by Genzyme, which acquired the world-wide 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 Europe. This was done to prevent off-label use of the drug to treat multiple sclerosis and to prepare for a higher-priced relaunch under the trade name Lemtrada, with a different dosage aimed at multiple sclerosis treatment.