Very simply the name CAMPATH derives from Cambridge Pathology. It was a name coined in the early 80s by Herman Waldmann's group then working in the Cambridge University, Department of Pathology. It was applied to a group of monoclonal antibodies being developed for clinical use.
Over the years there has been a lot of discussion about the use of monoclonal antibodies for the treatment of diseases. Antibodies have been termed so called 'magic bullets' because they can target specifically, cells, infectious agents or toxins, and then kill them, or mark them for destruction or removal from the body. Antibodies are of course a natural part of the immune defences of most higher animals and as such have evolved to be a sophisticated weapon in the biological 'arms race' escalation between pathogens and the hosts they infect.
My own research interests have always been in trying to work out the natural functions of antibodies and then trying to harness this knowledge in the design of better therapeutic strategies for the treatment of diseases using laboratory made monoclonal and recombinant antibodies. One (but not the only) successful outcome of this work has been the development of an antibody called CAMPATH-1H which is now undergoing the final phases of commercial development with the Biotechnology company LeukoSite (now merged with Millennium Pharmaceuticals Inc.). The following is a brief description (often anecdotal) outlining some of the background and in particular the role of the Cambridge University Pathology Department as well as my own involvment in the development of CAMPATH-1H and there are also links to other material available on the web.
It should be said right from the outset that a large number of scientists, clinicians, patients, technicians, lawyers, patent agents and others have been involved over about 20 years in getting CAMPATH-1H to it's present state. I hope that I have not offended anyone by either ommission or incorrect attribution in this version of the CAMPATH-1H story but if I have I apologise and I would of course wish to hear from you so that I can make ammends by correcting the information here. This is not meant to be definitive CAMPATH-1 story as to do that it would be necessary to involve at least two others in telling their parts in the development, they are of course Geoff Hale now scientific director of the Therapeutic Antibody Centre, Oxford, and Herman Waldmann, now Professor of the Sir William Dunn School of Pathology, University of Oxford. Geoff Hale and Herman Waldmann have recently published their own account of story (Hale & Waldmann 2000) but this is Mike's CAMPATH story.
The story really begins in about 1978. I joined César Milstein's laboratory, at the MRC Laboratory of Molecular Biology in Cambridge, in October 1978 to study for a PhD. At that time I met, in the laboratory, Herman Waldmann who was then on sabbatical leave from his lectureship in the Department of Pathology, learning the new technology for production of monoclonal antibodies. Towards the end of his period there Herman discussed plans to apply for an MRC programme grant to make monoclonal antibodies for the purpose of removing T-cells from human bone marrow to treat the problems of Graft-versus-Host disease. Herman returned to the Department of Pathology and was successful in his grant application to the MRC. One other fortunate piece of luck at the time was that Giovanni Galfre and Bruce Wright, also in César Milstein's laboratory, were at that time developing a rat myeloma line called Y3/Ag1.2.3 for making rat hybridomas and Herman Waldmann was one of the first people in the world to adopt this system for the production of antibodies to human cells.
When I finished my PhD research in 1981 I had initially intended to go to Oxford but a chance encounter with Herman Waldmann persuaded me to consider joining his new research programme on monoclonal antibodies for use in bone marrow transplantation. At that time Herman's research group seemed to provide an exciting prospect of learning some 'proper' immunology! Also in the laboratory at that time were a number of individuals with differing personalities and areas of expertise including Geoff Hale, Steve Cobbold, Sue Watt, Hoang Trang, Rose Zamoyska and Polly Matzinger. Shortly afterwards Don Metcalfe arrived from Australia for a sabbatical and many interesting discussions on immunology took place in the tea room! All of these people contributed important ideas or expertise to the projects which later led to production of CAMPATH-1
To start the programme Herman had collaborated with his colleague Alan Munro, then a Reader in Immunology in the Pathology Department, and had immunised rats with human T-cells and then performed the cell fusion with the rat myeloma Y3/Ag1.2.3. The fusion named YTH (Y3 x rat immunised with T-cells from Human) had been distributed into 96 culture wells and all had grown and most contained interesting antibody specificities. The early screening was conducted by Herman Waldmann's group in collaboration with Alan Munro's group and the first findings of an antibody YTH66.9 (rat IgM) which lysed human lymphocytes were published by Hale et al in 1983.
A key thing about the work had been the use of human complement mediated lysis to screen for functional killing of lymphocytes and as we found out later the choice of rat antibodies. YTH66.9 later became known as CAMPATH-1 and then later CAMPATH-1M to distinguish it from other similar antibodies. Over several years Geoff Hale and others in the laboratory developed the use of the IgM antibody for the in-vitro depletion of lymphocytes, using complement lysis, for the prevention of graft versus host disease. This application of YTH66.9 (CAMPATH-1M) proved highly successful in the clinic. Unfortunately it was found that when the IgM antibody was used in-vivo for the treatment of leukaemia that it was very inefficient at removing these cells despite the fact that it could activate complement.
My own early work in the laboratory was not directly on CAMPATH-1, but instead I worked on a CD3 antibody YTH12 (sometimes refered to as CAMPATH-3)and also on work to do with defining functions of rat IgG subclasses. I thus developed a panel of mouse monoclonal antibodies to rat IgG subclasses, under the fusion name NORIG (NSO x mouse immunised with Rat Ig). Two of these antibodies NORIG 7.16 and NORIG 1.1 turned out to be specific for rat IgG2b. Using these reagents and in collaboration with Professor Robin Coombs, then head of the Immunology Division, I developed some rapid assay systems based on agglutination of RBC coupled with the anti-rat subclass antibodies (Clark et al 1984) .
During the studies on antibody function Geoff Hale and I were able to show that for complement mediated lysis of cells the antigen specificity was as, or even more, important than the antibody isotype. But for antibody dependent cell mediated cytotoxicty (ADCC) the isotype was very important, and in fact rat IgG2b antibodies were the best, Hale et al (1985). At the time we had in the laboratory CAMPATH-1 antigen specific antibodies of the rat IgM class, the rat IgG2a subclass and the rat' IgG2c subclass but unfortunately not rat IgG2b. So Geoff Hale used the 'NORIG' anti-rat IgG2b antibodies on RBC to screen for very rare class switch variants of the rat IgG2a secreting hybridoma YTH34.5 (Hale et al 1987). The resulting rat IgG2b antibody was called CAMPATH-1G to distinguish it from the original rat IgM antibody which was thus called CAMPATH-1M
The rat IgG2b antibody CAMPATH-1G turned out to be a brilliant success. Early clinical studies in lymphoma and leukaemia patients showed that the antibody was highly effective at destroying lymphocytes in-vivo whereas the original rat IgG2a and rat IgM antibodies were not.
Whilst I had been a PhD student of César Milstein's in the Laboratory of Molecular Biology we had been joined by Michael Neuberger who had returned from a post-doctoral period in Germany with plans to work on the V-genes of an antibody with a well defined idiotype and specificity for the hapten NP. Over the next few years Michael cloned the V-genes and developed expression systems to allow him to express the NP-specific antibody as a chimaeric construct. Michael Neuberger was thus one of the first to become involved in the new science of antibody engineering. When Michael published this work I had left LMB and was then working in Herman Waldmann's group and I approached Michael to see if we could try to use his expression system to look at immunoglobulin function. At about this time we were in Herman Waldmann's group writing a proposal to renew the MRC programme grant for a further 5 years and, together with Herman, I wrote a proposal to express matched sets of recombinant human antibodies to study their effector functions in well controlled experiments. The grant application was successful and in fact the laboratory was joined by a post-doctoral scientist Marianne Bruggemann whom Michael Neuberger had met whilst in Germany. In a collaboration between our two laboratories in Cambridge, Michael and Marianne set about making the first complete matched set of recombinant human antibodies with a single defined specificity (to the hapten NP) including human IgM, IgA, IgE and IgG1, IgG2 IgG3 and IgG4. We were thus able to use these antibodies to study human effector functions and we then also made them generally available to other laboratories for their own further studies (Bruggemann et al 1987).
A second set of chimaeric antibodies prepared by Marianne was a chimaeric set of rat antibodies to the hapten NP. Using the chimaeric series we were able to confirm that rat IgG2b antibodies were very good at interacting with human effector mechanisms and also that the human IgG1 isotype was probably the best human isotype to achieve similar effects.
The early uses of CAMPATH-1G were in lymphoma and leukaemia patients. These diseases frequently involve a loss of normal lymphoid cells and hence are generally accompanied by a lack of immune function. Generally antibody therapy with CAMPATH-1G was limited to 10 day courses of antibody and there were no major problems with the patients making antibodies to the administered rat immunoglobulin. Some patients received repeat courses of antibodies without making significant anti-rat immune responses.
In contrast when the antibody started to be used for general immunosuppression in organ transplant patients (kidney and liver) it was observed that a majority of patients made an antiglobulin response after about 10-15 days from the start of therapy. This limited the usefulness of the antibody to perhaps only a single course of therapy. Repeated use of the antibody would run the risk that the patients antiglobulin response would the block the activity of the antibody or worse still might cause an allergic (anaphalactic) response.
In fact antiglobulin responses to rodent antibodies were starting to be observed as a key problem in the use of many different mouse and rat monoclonal antibodies in therapy, not just CAMPATH-1G. Some groups started to tackle this problem by making use of the kind of technology developed by Michael Neuberger and Marianne Bruggemann and constructed chimaeric antibodies with rodent V-regions and human C-regions.
In fact Michael Neuberger had joined forces with Greg Winter also of the Laboratory of Molecular Biology. They decided that not only would it be possible to make chimaeric constructs with rodent V-regions and human C-regions but that the V-region itself could be made more human like by transferring the rodent complmentarity determining regions onto the human framework regions. This new technology was called antibody 'V-region reshaping' or humanisation and it was hoped that this could provide less immunogenic antibodies. For their first antibody Greg Winter's group in collaboration with Michael Neuberger set about humanising the hapten-NP specific antibody heavy chain V-region.
When Herman Waldmann and I heard about the humanisation of NP by Greg Winter's group we immediately decided to contact him and persuade him to collaborate on a project to humanise another antibody of real clinical importance. We had sufficient evidence to know that CAMPATH-1G worked in vivo but that it's full potential was limited by the patients anti-globulin response to the rat specific sequences. Greg Winter agreed to a collaboration on this project and I started work in about 1986, together with Lutz Riechmann in Greg Winter's laboratory on the cloning, humanisation and expression of a recombinant form of CAMPATH-1G.
This project involved humanisation of an antibody to a cell surface glycoprotein antigen of unknown structure and thus posed additional problems to the humanisation of the anti-hapten antibody. We decided to tackle the project with several parallel strategies. First I prepared a heavy chain loss variant of CAMPATH-1G whilst Lutz cloned the rat heavy and light chain V-regions from the same cell line. Lutz then prepared chimaeric constructs with the rat heavy chain V-region and the four human IgG subclass constant regions for IgG1, IgG2, IgG3 and IgG4. These were expressed by transfecting them into the variant cell line making the rat light chain. The idea was that they would all have the same binding affinity as the starting rat antibody and we could thus assess the activity of the antibodies in effector assays based on a comparison of the human subclasses with rat IgG2b which we knew was effective in vivo.
The humanisation of Campath-1G to give Campath-1H proved to be successful although it proved necessary to make some changes to framework residues in order to restore binding activity to desired levels. Campath-1H was thus the first fully humanised antibody (humanised immunoglobulin heavy and light chain) against a protein antigen, against a cell surface molecule and of therapeutic potential. The results of this in-vitro work were reported in an article in Nature (Riechmann et al 1988).
The next step was to prepare therapeutic grade material for clinical testing. Most of this work was carried out in the Department of Pathology by Dr Jenny Phillips, culturing many litres of the transfectant cell line in roller flasks and then purifying the antibody using protein A. Enough antibody was prepared to successfully treat two lymphoma patients and this work was reported in The Lancet (Hale et al 1988). A further pioneering clinical study using this humanised antibody to treat a patient with an autoimmune condition (vasculitis) was also carried out by the late Dr Martin Lockwood and this study was also reported in The Lancet (Mathieson et al 1990).
The University of Cambridge and the Medical Research Council assigned the humanised antibody Campath-1H to the organisation BTG who had previously been assigned the rat antibodies Campath-1M and Campath-1G. BTG were responsible for filing patents on these antibodies and their clinical uses and for the sub-licensing to a pharmaceutical company.
Campath-1H then proved to have a somewhat chequered passage into commercial development. BTG licensed the antibody to the pharmaceutical company Wellcome Plc (which later merged with Glaxo Pharmaceuticals Plc to form Glaxo-Wellcome). Several changes were made to the antibody in particular it was re-expressed as a cDNA construct in CHO cells and which were adapted to large scale culure airlift fermenters. The project seemed to progress very well over a number of years and clinical trials were carried out firstly in lymphoma and leukemia and then extending into autoimmunity (Rheumatoid Arthritis). Despite very encouraging results in some forms of lymphocytic leukemia and lymphoma there were some problems encountered in the use of the antibody in immunosuppression of rheumatoid arthritis patients. At a late stage, the end of phase III clinical trials, Glaxo-Wellcome took the commercial decision to abandon the whole Campath project.
Thus the antibody was once again available for relicensing by BTG. Herman Waldmann put BTG in contact with LeukoSite and they eventually were able to negotiate a new licensing deal with BTG for CAMPATH-1H. LeukoSite continued the development of CAMPATH-1H and repeated some of the clinical trials. Then in late 1999 LeukoSite and Millennium Pharmaceuticals Inc announced a merger. The company then filed a Biologics Licensing Application (BLA) with the FDA in April 2000.
Millennium Pharmaceuticals announced in a press release on 8th May 2001 "The U.S. Food and Drug Administration (FDA) today cleared Campath® (alemtuzumab) humanized monoclonal antibody for marketing as a treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL) who have been treated with alkylating agents and have failed fludarabine therapy."
Further information on the FDA approval and the clinical uses of this antibody known as Campath® or by the generic drug name Alemtuzumab can be obtained from the website
Following marketing approval of Campath® (alemtuzumab), Millennium Pharmaceuticals entered into an agreement with ILEX Oncology such that they were then entirely responsible for the continued post marketing development of the antibody. Later, in December 2004, Ilex Oncology Inc was acquired by Genzyme Inc and the production and further development of Campath® (alemtuzumab) is now detailed on the Genzyme Oncology website.
The text and illustrations on this web page are © copyright 2000, 2001, 2002, 2005 M.R. Clark, PhD., Lecturer in Therapeutic and Molecular Immunology, Department of Pathology, Cambridge University, Cambridge UK CB2 1QP. The information provided is to the best of my knowledge correct but if you are aware of any errors please do contact me.
Mike Clark