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 targets CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells 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 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. ^{[1] [2]}

A significant 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).^[3]

Research or off-label use

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.^[4] Promising results were reported in 2011 from a phase III trial against Rebif.^[2]

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.^[5]

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.^[6] 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.^[7]

Campath is marketed in the United States and Canada by Genzyme.

References

1. ^ "Drug may reverse MS brain damage". 22 Oct 2008. http://news.bbc.co.uk/1/hi/health/7680641.stm. 
2. ^ ^{a b} "Sanofi and Genzyme Report New Positive Data from First Phase III Study with MS Drug". 24 Oct 2011. http://www.genengnews.com/gen-news-highlights/sanofi-and-genzyme-report-new-positive-data-from-first-phase-iii-study-with-ms-drug/81245853/. 
3. ^ http://www.campath.com/hcp/AboutCampath.html
4. ^ Drug reboots immune system to reverse MS, Andy Coghlan, New Scientist News Service, October 23, 2008.
5. ^ Successful treatment of severe acute intestinal graft-versus-host resistant to systemic and topical steroids with alemtuzumab., Schnitzler M, Biol Blood Marrow Transplant. 2009 Aug;15(8):910-8.
6. ^ Hale G, Bright S, Chumbley G, Hoang T, Metcalf D, Munro AJ, Waldmann H. Removal of T cells from bone marrow for transplantation: a monoclonal antilymphocyte antibody that fixes human complement. Blood 1983;62:873-82. PMID 6349718.
7. ^ Riechmann L, Clark M, Waldmann H, Winter G. Reshaping human antibodies for therapy. Nature 1988;332:323-7. doi:10.1038/332323a0 PMID 3127726.

External links

• Full Prescribing Information
• Mike Clark's Campath story
• From laboratory to clinic: the story of CAMPATH-1 (Geoff Hale and Herman Waldmann)
• Fact Sheet about Alemtuzamab (Campath)