The story of Campath-1H in multiple sclerosis
By Dr. Alasdair Coles, Department of Neurology
Addenbrooke's Hospital, Cambridge, UK
Multiple Sclerosis Society
The history of Campath-1H
In Cambridge, UK, in the 1970s a great breakthrough was made. Kohler and Milstein discovered a way of making antibodies, for which they would later receive the Nobel Prize. Their technique was special in two ways. First, they used a cell system which meant that the antibodies could be made perpetually. Secondly, the antibodies could be made 'monoclonal' so that the immortalised cells produce antibodies that all target the same molecule. This specificity led to their nickname, "magic bullets". Many drugs have been made using this technique, including Antegren (natalizumab) for multiple sclerosis.
Just opposite Kohler and Milstein's laboratory was Addenbrooke's Hospital and it was here that the prototype therapeutic monoclonal antibodies were first put to clinical use. One of these was Campath-1H , an antibody that was extraordinarily effective at killing lymphocytes, which are a subset of the white cells in the blood that makes up the immune system
Initially it was used in conditions where lymphocytes are overproduced, such as leukaemias and lymphomas. It is now a licensed treatment for B cell chronic lymphocytic leukaemia
Campath-1H in progressive multiple sclerosis: 1991-8
By the early 1990s, doctors in Cambridge began to experiment with using Campath-1H in autoimmune diseases, such as rheumatoid arthritis and vasculitis. So it was that, in 1991, the first person with multiple sclerosis was treated using Campath-1H. She, and the next 35 patients, had secondary progressive multiple sclerosis. At one level, Campath-1H was very effective: it dramatically reduced relapse rate and new MRI lesion formation.(1,2,3). However, it had very little effect on the progression of their disability. We concluded, as many other people were doing at the time for other reasons, that the progressive phase of multiple sclerosis is not due to inflammation and therefore not amenable to anti-inflammatory treatments. Instead the progressive phase of multiple sclerosis is probably due to the slow death of nerve cells themselves.
The critical issue for the treatment of multiple sclerosis is whether this death of nerve cells can be prevented. At present, all we have available to us are drugs that act on the immune system to suppress inflammation and demyelination. Now, we believe that nerve cells die off in multiple sclerosis because they have lost the beneficial effects of their myelin wrapping. In which case, if we can suppress inflammation early enough, and prevent too much demyelination, we should be able to stop nerve cell death. This is a hypothesis only. Some neurologists think multiple sclerosis is primarily a disease where nerve cells are destined to die, and that the inflammation we see in the brain is secondary; in which case no anti-inflammatory treatment will prevent the progressive phase of multiple sclerosis.
Campath-1H in relapsing-remitting multiple sclerosis: 1998-2003
Our idea then is that, in order to prevent the progressive phase of multiple sclerosis, we need not only to suppress relapses, but also we need to do it early on in the disease course. We have used Campath-1H on 17 people with early relapsing-remitting multiple sclerosis so far. They had multiple sclerosis for an average of 1.8 years each and had experienced a mean of 2.8 relapses a year (4). We have been following-up these patients for just over a year and have documented just two relapses in total (0.088 per patient). We do not yet know whether we have prevented the onset of the progressive phase in this group.
This experience has encouraged us to set up a formal study of Campath-1H in early relapsing-remitting multiple sclerosis: the CAMMS223 trial. People are randomised to receive either Campath-1H (in one of two doses) or an interferon-beta. This trial is up and running, with trial centres in Cambridge in the UK, as well as at thirty sites in the United States, in Italy and in Eastern Europe. It is funded by an American company called Ilex Oncology.
We are still recruiting people whose first attack must have been less than three years ago with at least two attacks in the last two years, and who are still able to walk without assistance. Because we are comparing Campath-1H with beta-interferon, we cannot include anyone who has already had treatment with this drug, or indeed any immunosuppressant. The trial period is for three years followed by a further assessment after another two years. Monitoring will be mainly done by clinical examinations every three months (using the famous Kurtzke score among others). In addition everyone will have an annual MRI scan looking for signs of demyelination and nerve damage. (Research trials recruitment ; Controlled trials). The first set of results from this study should be available in 2006.
The side-effects of Campath-1H
Even though Campath-1H holds promise for the treatment of multiple sclerosis, it has its problems. The first dose of the drug may cause a headache, rash, fever and malaise, as well as transiently worsen peoples' multiple sclerosis symptoms (David's story ) (5) For unknown reasons, it causes Graves' disease in one third of the people (6). This is an autoimmune disease, like multiple sclerosis, that attacks the thyroid gland leading to an overactive thyroid. Tablets usually control this. Also people may be vulnerable to infections after Campath-1H.
Because these are quite significant side-effects compared to those of interferon-beta, the CAMMS223 trial will have to demonstrate that Campath-1H offers a significant advantage over the current licensed therapies before it will be considered a useful treatment in multiple sclerosis.
1: Moreau T, Thorpe J, Miller D, Moseley I, Hale G, Waldmann H, Clayton D, Wing M, Scolding N, Compston A. Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis. Lancet. 1994 Jul 30;344(8918):298-301.
2: Paolillo A, Coles AJ, Molyneux PD, Gawne-Cain M, MacManus D, Barker GJ,Compston DA, Miller DH. Quantitative MRI in patients with secondary progressive MS treated with monoclonal antibody Campath 1H.Neurology. 1999 Sep 11;53(4):751-7.
3: Coles AJ, Wing MG, Molyneux P, Paolillo A, Davie CM, Hale G, Miller D,Waldmann H, Compston A. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol. 1999 Sep;46(3):296-304.
4: Compston A, Coles A. Presented at the 2003 meeting of the Association of American Neurologists.
5: Moreau T, Coles A, Wing M, Isaacs J, Hale G, Waldmann H, Compston A. Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis. Brain. 1996 Feb;119 ( Pt 1):225-37.
6. Coles AJ, Wing M, Smith S, Coraddu F, Greer S, Taylor C, Weetman A, Hale G,Chatterjee VK, Waldmann H, Compston A. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet. 1999 Nov 13;354(9191):1691-5
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